Cyclic peptide modulators of fcrn and uses thereof

Abstract

Provided herein are cyclic peptides capable of binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins, and methods of using the same for the treatment and / or prevention of various diseases, including conditions associated with FcRn activity and / or immunoglobulin G (IgG) autoantibody levels in a subject.

Description

[0001] CYCLIC PEPTIDE MODULATORS OF FCRN AND USES THEREOF

[0002] RELATED APPLICATIONS

[0003] [1] The present application claims priority under 35 U. S. C. § 119(e) to United States Provisional Patent Application, U. S. S. N. 63 / 723,409, fded November 21, 2024, United States Provisional Patent Application, U. S. S. N. 63 / 846,017, fded July 17, 2025, and United States Provisional Patent Application, U. S. S. N. 63 / 891,264, fded September 30, 2025, the entire contents of each of which are incorporated herein by reference.

[0004] BACKGROUND

[0005] [2] The neonatal fragment crystallizable receptor (FcRn) plays an important role in extending the halflife of immunoglobulin G (IgG) autoantibodies, which are associated with numerous pathological conditions in subjects including autoimmune diseases. Because inhibition of FcRn can modulate IgG half-life, FcRn inhibitors are useful for the treatment of various diseases and conditions, such as IgG-mediated autoimmune and inflammatory conditions. See, e.g., Low and Mezo, “Inhibitors of the FcRmlgG Protein-Protein Interaction” 2009, The AAPS Journal, vol. 11, no. 3, pp. 432-434; Pyzik et al. “The therapeutic age of the neonatal Fc receptor” 2023, Nature Reviews Immunology, vol. 23, pp. 415— 432. Examples of peptide inhibitors of FcRn can be found in, e.g., International PCT Application Publication Nos. WO 2007 / 098420, WO 2009 / 020867, and WO 2010 / 014909. Agents capable of modulating FcRn activity have therapeutic promise in the treatment of various diseases.

[0006] SUMMARY

[0007] [3] Provided herein are cyclic peptides capable of binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins, and methods of using the same for the treatment and / or prevention of various diseases, including conditions associated with FcRn activity and / or immunoglobulin G (IgG) autoantibody levels in a subject. In some embodiments, cyclic peptides (and dimers thereof) described herein do not induce a histamine response in subject, or induce a reduced histamine response in a subject compared with other cyclic peptide inhibitors of FcRn.

[0008] [4] In one aspect, provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising the amino acid sequence:

[0009] X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(REF ID NO: 1), wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein.

[0010] [5] In certain embodiments, provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising the amino acid sequence:

[0011] X1-X2-Pen*-X4-G-X6-X7-X8-X9-X10-Y-P-C* (REF ID NO: 2), wherein Pen is penicillamine; * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink; and X1, X2, X4, X6, X7, X8, X9, X10are as described herein.

[0012] [6] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises one of the following amino acid sequences:

[0013] REF REF ID Sequence ID Sequence

[0014] NO NO

[0015] 3 F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 4 [< -F-Pcn*-T-G-EI-F-G-Sar-NMcL-Y-P-C* 5 R-F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 6 R-F-Pen*-Kt-G-H-F-G-Sar-NMeDt-Y-P-C* 7 R-F-Pcn*-K -G-H-F-G-Sar-NMcE -Y-P-C* 8 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 9 N-F-Pen*-T-G-H-F-G-X9B-NMeL-Y-P-C* 10 N-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 11 N-F-Pen*-T-G-H-X7A-G-Sar-NMeL-Y-P-C* 12 L-F-Pen*-T-G-H-X7A-G-Sar-NMeL-Y-P-C* 13 L-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 14 N-F-Pen*-T-G-H-F-G-X9C-NMeL-Y-P-C* 15 L-F-Pen*-T-G-H-F-G-X9C-NMeL-Y-P-C* 16 Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 17 N-F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 18 F-Pcn*-K -G-EI-F-G-Sar-NMcE -Y-P-C* 19 R-F-Pcn*-I< -G-H-F-G-X9' -NMcE -Y-P-C* 20 K -F-Pcn*-K -G-E[-F-G-Sar-NMcE -Y-P-C* 21 N-F-Pcn*-I< -G-EI-X '-G-Sar-NMcE -Y-P-C* 22 N-F-Pen*-T-G-X6A-F-G-Sar-NMeL-Y-P-C* 23 N-F-Pen*-T-G-X6A-F-G-X9C-NMeL-Y-P-C* 24 N-F-Pen*-T-G-X6B-F-G-Sar-NMeL-Y-P-C* 25 F-Pen*-T-G-X6A-F-G-Sar-NMeL-Y-P-C* 26 F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-P-C* 98 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P-C* 99 N-F-Pen*-X4At-G-X6C-F-G-IDA-NMeEt-Y-P-C* 100 Xl'-F-Pcn*-E -G-X6' -F-G-IDA-NMcI< -Y-P-C* 101 N-F-Pcn*-Xl' -G-X6' -F-G-Sar-NMcE -Y-P-C* 102 N-F-Pcn*-Xl' -G-X6l,-F-G-Sar-NMcE -Y-P-C* 103 X1A-X2A-Pen*-X4At-G-X®-F-G-Sar-NMeEt-Y-P- C*

[0016] 104 N-F-Pen*-X4At-G-X®-F-G-IDA-NMeEt-Y-P-C* 105 Xl'-F-Pcn*-Xl' -G-X6l,-F-G-Sar-NMcE -Y-P-C* 106 Xl'-F-Pcn*-Xl' -G-X'l,-F-G-IDA-NMcE -Y-P- 107 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P-C*

[0017] C*

[0018] 220 D-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 221 R-F-Pen*-Et-G-H-F-G-Sar-NMeKt-Y-P-C* 222 R-F-Pen*-K-G-H-F-G-Sar-NMeL-Y-P-C* 223 X1A-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 224 Q-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 225 Q-F-Pen*-T-G-H-X7A-G-Sar-NMeL-X11A-P-C* 226 N-F-Pen*-T-G-H-X7B-G-Sar-NMeL-Y-P-C* 227 (D-Leu)-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 228 (D-Asn)-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 229 R-F-Pen*-T-G-X6E-F-G-Sar-NMeL-Y-P-C* 230 R-F-Pe^-T-G-X^-F-G-Sar-NMeL-Y-P-C* 231 Xl'-F-Pcn*-Xl' -G-X6 i-F-G-IDA-NMcE -Y-P-C* 232 R-F-Pen*-T-G-X®-X7C-G-Sar-NMeL-Y-P-C* 233 R-F-Pen*-T-G-X®-X7D-G-Sar-NMeL-Y-P-C* 234 Xl'-F-Pcn*-Xl' -G-X9l l-F-G-IDA-NMcE -Y-P-C* 235 X1A-F-Pen*-X4At-G-X6I-F-G-IDA-NMeEt-Y-P-C* 236 X1A-F-Pen*-X4At-G-X®-F-G-X9D-NMeEt-Y-P-C* 237 X1A-F-Pen*-X4At-G-X6C-X7E-G-IDA-NMeEt-Y-P- C*

[0019] 238 X1A-F-Pen*-X4At-G-X6C-F-G-X9D-NMeEt-Y-P-C* 239 X1A-F-Pen*-X4At-G-X6D-F-G-X9E-NMeEt-Y-P-C* 240 X1A-F-Pen*-X4At-G-X6D-F-G-X9F-NMeEt-Y-P-C* 241 X1A-F-Pen*-X4At-G-X6C-F-G-X9F-NMeEt-Y-P-C* 242 X1A-F-Pen*-X4At-G-X6C-F-G-X9E-NMeEt-Y-P-C* 243 X1A-F-Pen*-X4At-G-X®-F-G-X9G-NMeEt-Y-P-C* 244 X1A-F-Pen*-X4At-G-X®-F-G-X9H-NMeEt-Y-P-C* 245 R-F-Pen*-T-G-X6I-F-G-Sar-NMeL-Y-P-C* 246 R-F-Pen*-T-G-X6K-F-G-Sar-NMeL-Y-P-C* 247 R-F-Pen*-T-G-X6C-X7F-G-Sar-NMeL-Y-P-C* 248 Xl'-F-Pcn*-E -G-X9l-Xi-G-IDA-NMcI< -Y-P-C* 249 X1A-F-Pen*-X4At-G-Xa-X7G-G-IDA-NMeEt-Y-P- C*

[0020] 250 Xl'-F-Pcn*-Xl' -G-X6l-F-G-IDA-NMcE -Y-P-C* 251 Xl'-F-Pcn*-Xl' -G-X9l-F-G-IDA-NMcE -Y-P-C* 252 X1A-F-Pen*-X4A^-G-X6F-F-G-IDA-NMeE^-Y-P-C* 253 X1A-F-Pen*-X4At-G-X6M-F-G-IDA-NMeEt-Y-P- C*

[0021] 254 Xl'-F-Pcn*-Xl' -G-X,?-F-G-IDA-NMcE -Y-P-C* 255 E-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 256 R-F-Pen*-N-G-H-F-G-Sar-NMeL-Y-P-C* 257 (D-Asn)-F-Pen*-T-G-H-X7B-G-Sar-NMeL-Y-P-C* 258 X1A-F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 259 X1A-F-Pen*-Et-G-X6C-F-G-IDA-NMeKt-Y-X12A- C*

[0022] 260 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y- 261 X1A-F-Pen*-Et-G-X6C-F-G-X9I-NMeKt-Y-P-C*

[0023] X12A-C*

[0024] 262 X1A-F-Pen*-Et-G-X6C-F-G-X9J-NMeKt-Y-P-C* 263 Xl'-F-Pcn*-Xl' -G-X6' -F-G-X9l-NMcE -Y-P-C* 264 Xl'-F-Pcn*-Xl' -G-X6' -F-G-X9l-NMcE -Y-P-C* 265 X1A-F-Pen*-X4At-G-X®-F-G-X9A-NMeEt-Y-P-C* 266 X1A-F-Pen*-X4At-G-X®-F-G-X9K-NMeEt-Y-P-C* 267 Xl'-F-Pcn*-Xll' -G-X6' -F-G-IDA-NMcI< -Y-P-C* 268 Xl''-F-Pcn*-Xl'' -G-X6' -XG I-G-IDA-NMcE -Y-P- 269 Xl'-F-Pcn*-Xl' -G-X6,-F-G-IDA-NMcE -Y-P-C*

[0025] C*

[0026] 270 Xl'-F-Pcn*-E -G-X'l-F-G-IDA-NMcI< -Y-P-C* 271 Xl'-F-Pcn*-E -G-XA I-F-G-IDA-NMcI< -Y-P-C* 272 Xl'-F-Pcn*-E -G-X, l-F-G-IDA-NMcI< -Y-P-C* 273 Xl'-F-Pcn*-E -G-X6l-F-G-IDA-NMcI< -Y-P-C* 274 X1A-F-Pen*-X4At-G-X6C-F-G-X9L-NMeEt-Y-P-C* 284 X1A-F-Pen*-X4B-G-X6D-F-G-Sar-NMeL-Y-P-C* 285 R-F-Pen*-T-G-H-X7I-G-Sar-NMeL-Y-P-C* 286 R-F-Pen*-T-G-X6P-F-G-Sar-NMeL-Y-P-C* 287 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12B-C* 288 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12C-C*

[0027]

[0028] 289 R-F-Pen*-T-G-X6Q-F-G-Sar-NMeL-Y-P-C* 290 Ki-F-Pen*-X4C-G-H-F-G-Sar-NMeL-Y-P-C*i REF REF

[0029] ID Sequence ID Sequence

[0030] NO NO

[0031] 291 I< -F-Pcn*-XIA-G-H-F-G-Sar-NMcE -Y-P-C* 292 R-F-Pen*-T-G-X6R-F-G-Sar-NMeL-Y-P-C* 293 R-F-Pen*-T-G-H-X7I-G-Sar-NMeL-Y-P-C* 294 R-F-Pen*-T-G-H-F-G-Sar-NMeL-X11B-P-C* 295 R-F-Pen*-T-G-H-X7K-G-Sar-NMeL-Y-P-C* 296 R-F-Pen*-T-G-H-X7M-G-Sar-NMeL-Y-P-C* 297 R-F-Pen*-Kt-G-H-F-G-IDAt-NMeL-Y-P-C* 298 R-F-Pen*-T-G-H-X7N-G-Sar-NMeL-Y-P-C* 299 K -F-Pcn*-I< -G-X6'-F-G-Sar-NMcE -Y-P-C* 300 R-F-Pen*-T-G-H-X70-G-Sar-NMeL-Y-P-C* 301 R-F-Pen*-T-G-H-X7Q-G-Sar-NMeL-Y-P-C* 302 R-F-Pen*-T-G-X6S-F-G-Sar-NMeL-Y-P-C* 303 I< -F-Pcn*-I< -G-X6'-F-G-X9' -NMcL-Y-P-C* 304 R-F-Pen*-T-G-X6T-F-G-Sar-NMeL-Y-P-C* 305 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12D-C* 306 R-F-Pen*-T-G-H-Y-G-Sar-NMeL-Y-P-C* 307 R-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 308 (D-Arg)-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y- P-C*

[0032] 309 R-F-Pen*-T-G-X6U-F-G-Sar-NMeL-Y-P-C* 310 X1A-Pen*-X4Y-G-H-F-G-Sar-NMeL-Y-P-C* 311 X1A-F-Pen*-Et-G-X6C-F-G-X9Mt-NMeL-Y-P-C* 312 N-F-Pen*-T-G-H-F-G-IDA-NMeL-Y-P-C* 313 R-F-Pen*-T-G-H-X7R-G-Sar-NMeL-Y-P-C* 314 [< -X2' '-Pcn*-I< -G-H-F-G-Sar-NMcE -Y-P-C* 315 X1A-F-Pen*-Et-G-H-F-G-Sar-X10At-Y-P-C* 316 F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 317 F-Pen*-T-G-H-F-G-X9N-NMeL-Y-P-C* 318 I< -F-Pcn*-I< -G-X6'-F-G-X9,-NMcE -Y-P-C* 319 Xl'-F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 320 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12E-C* 321 X1D-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 322 Kl-F-Pen*-Kt-G-H-F-G-X9At-NMeL-Y-P-C*t 323 (D-Arg)-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 324 R-F-Pcn*-D -G-H-F-G-Sar-NMcK -Y-P-C* 325 R-F-Pen*-T-G-H-X7S-G-Sar-NMeL-Y-P-C* 326 R-F-Pen*-T-G-X6V-F-G-Sar-NMeL-Y-P-C* 327 F-Pen*-X4D-G-H-F-G-Sar-NMeL-Y-P-C* 328 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Xllc-P-C* 329 X2B-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 330 R-F-Pen*-T-G-H-X7T-G-Sar-NMeL-Y-P-C* 331 R-F-Pen*-T-G-H-X7U-G-Sar-NMeL-Y-P-C* 332 R-F-Pen*-T-G-H-F-G-Sar-NMeL-X11D-P-C* 333 R-F-Pen*-T-G-H-X7V-G-Sar-NMeL-Y-P-C* 334 R-F-Pen*-T-G-H-X7W-G-Sar-NMeL-Y-P-C* 335 R-F-Pen*-K-G-H-F-G-Sar-NMeE-Y-P-C* 336 Xl l5-F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 337 R-F-Pen*-T-G-X6ZA-F-G-Sar-NMeL-Y-P-C* 338 XI A-F-Pcn*-I< -G-H-F-G-X,,,-NMcE -Y-P-C* 339 R-F-Pen*-T-G-H-X7X-G-Sar-NMeL-Y-P-C* 340 R-F-Pen*-T-G-H-X7Y-G-Sar-NMeL-Y-P-C* 341 F-Pen*-T-G-H-F-G-X9P-NMeL-Y-P-C* 342 N-F-Pcn*-E -G-H-F-G-Sar-NMcK -Y-P-C* 343 X1D-F-Pen*-K^-G-H-F-G-Sar-NMeE^-Y-P-C* 344 R-F-Pen*-T-G-H-X7Z-G-Sar-NMeL-Y-P-C* 345 Pcn*-K -G-H-F-G-Sar-NMcE -Y-P-C* 346 R-F-Pen*-T-G-H-X7AA-G-Sar-NMeL-Y-P-C* 347 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12F-C* 348 R-F-Pen*-T-G-H-X7AV-G-Sar-NMeL-Y-P-C* 349 R-F-Pen*-K-G-H-F-G-Sar-NMeD-Y-P-C* 350 X|,-F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 351 N-F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 352 R-F-Pcn*-E -G-H-F-G-Sar-K -Y-P-C* 353 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12G-C* 354 R-F-Pen*-T-G-H-X7L-G-Sar-NMeL-Y-P-C* 355 X2C-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 356 R-F-Pen*-T-G-H-F-G-IDA-NMeL-Y-P-C* 357 X1A-F-Pen*-X4Y-G-H-F-G-Sar-NMeL-Y-P-C* 358 R-F-Pen*-T-G-X6W-F-G-Sar-NMeL-Y-P-C* 359 R-F-Pen*-T-G-X6X-F-G-Sar-NMeL-Y-P-C* 360 R-F-Pen*-T-G-X6ZB-F-G-Sar-NMeL-Y-P-C* 361 F-Pcn*-I< -G-H-F-G-X9l<-NMcE -Y-P-C* 362 XIA-F-Pcn*-I< -G-H-F-G-Sar-E -Y-P-C* 363 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12H-C* 364 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12A-C* 365 X1A-F-Pen*-X4D-G-H-F-G-Sar-NMeL-Y-P-C* 366 R-F-Pcn*-XIA-G-H-F-G-Sar-NMcE -Y-P-C* 367 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12I-C* 368 L-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 369 (D-Leu)-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y- 370 R-F-Pen*-T-G-X6Y-F-G-Sar-NMeL-Y-P-C*

[0033] P-C*

[0034] 371 R-F-Pen*-T-G-H-X7AB-G-Sar-NMeL-Y-P-C* 372 R-F-Pen*-T-G-X6Z-F-G-Sar-NMeL-Y-P-C* 373 XIA-F-Pcn*-E -G-H-F-G-Sar-NMcI< -Y-P-C* 374 R-F-Pcn*-E -G-H-F-G-X9 l-NMcL-Y-P-C* 375 N-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 376 R-F-Pen*-T-G-X6AA-F-G-Sar-NMeL-Y-P-C* 377 R-F-Pen*-T-G-H-X7AC-G-Sar-NMeL-Y-P-C* 378 R-F-Pen*-T-G- X6C-F-G-Sar-NMeL-Y-P-C* 379 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-P-C* 380 X1A-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 381 R-F-Pen*-T-G-X6AB-F-G-Sar-NMeL-Y-P-C* 382 F-Pcn*-I< -G-H-F-G-X9,-NMcE -Y-P-C* 383 R-F-Pen*-T-G-H-X7AD-G-Sar-NMeL-Y-P-C* 384 R-F-Pen*-T-G-H-F-G-X9R-NMeL-Y-P-C* 385 R-F-Pen*-T-G-H-X7AE-G-Sar-NMeL-Y-P-C* 386 R-F-Pen*-T-G-X6AC-F-G-Sar-NMeL-Y-P-C* 387 R-F-Pen*-T-G-H-X7AF-G-Sar-NMeL-Y-P-C* 388 (D-Asn)-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y- P-C*

[0035] 389 R-F-Pen*-T-G-H-X7AG-G-Sar-NMeL-Y-P-C* 390 R-F-Pen*-X4D-G-H-F-G-Sar-NMeL-Y-P-C* 391 F-Pen*-T-G-H-F-G-X9S-NMeL-Y-P-C* 392 R-F-Pen*-T-G-X6AD-F-G-Sar-NMeL-Y-P-C* 393 R-F-Pen*-T-G-H-F-G-X9S-NMeL-Y-P-C* 394 R-F-Pen*-X4B-G-X6D-F-G-Sar-NMeL-Y-P-C* 395 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12I-C* 396 R-F-Pen*-T-G-X6AE-F-G-Sar-NMeL-Y-P-C*

[0036]

[0037] 397 R-F-Pen*-T-G-X6AF-F-G-Sar-NMeL-Y-P-C* 398 R-F-Pcn*-E -G-XAI,-F-G-X9 l-NMcL-Y-P-C* REF REF

[0038] ID Sequence ID Sequence

[0039] NO NO

[0040] 399 X1A-F-Pen*-Et-G-X®-F-G-X9Mt-NMeL-Y-P-C* 400 Xl'-F-Pcn*-Xl' -G-X6' -F-G-Sar-NMcE -Y-P-C* 401 R-F-Pen*-T-G-X6AG-F-G-Sar-NMeL-Y-P-C* 402 R-F-Pen*-T-G-X6AH-F-G-Sar-NMeL-Y-P-C* 403 R-F-Pen*-T-G-X®-X7AE-G-Sar-NMeL-Y-P-C* 404 Xl'-F-Pcn*-E -G-Xzl,-F-G-Sar-NMcI< -Y-P-C* 405 N-F-Pcn*-E -G-X6l,-F-G-Sar-NMcI< -Y-P-C* 406 Xl'-F-Pcn*-E -G-X6' -F-G-Sar-NMcI< -Y-P-C* 407 N-F-Pcn*-E -G-X'' -F-G-IDA-NMcI< -Y-P-C* 408 R-F-Pen*-T-G-X6C-X7AE-G-Sar-NMeL-Y-P-C* 409 N-F-Pcn*-E -G-X'l,-F-G-IDA-NMcI< -Y-P-C* 410 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P- Pen*

[0041] 411 Xl'-F-Pcn*-E -G-X6l,-F-G-IDA-NMcI< -Y-P-C* 412 Xl''-F-Pcn*-Xl'' -G-X6' -X ''l l-G-IDA-NMcE -Y- P-C*

[0042] 413 X1A-F-Pen*-X4At-G-X®-X7H-G-Sar-NMeEt-Y-P- 414 Kl-F-Pen*-X4At-G-X6C-F-G-IDA-NMeEt-Y-P-C*t C*

[0043] 415 R-F-Pen*-T-G-X6AI-F-G-Sar-NMeL-Y-P-C* 416 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-X12K-C* 417 Xl''-F-Pcn*-Xl'' -G-X6' -X, i-G-IDA-NMcE -Y-P- 418 X1A-F-Pen*-X4At-G-X6C-X7AI-G-IDA-NMeEt-Y-P- C* C*

[0044] 419 Xl''-F-Pcn*-Xl'' -G-X6''-X ''l-G-IDA-NMcE -Y- 420 Xl''-F-Pcn*-Xl' -G-X6'l-F-G-IDA-NMcE -Y-P- P-C* C*

[0045] 421 Xl''-F-Pcn*-Xl'' -G-X6' -X ''l-G-Sar-NMcE -Y-P- 422 Xl'-F-Pcn*-Xl' -G-X6'K-F-G-IDA-NMcE -Y-P- C* C*

[0046] 423 Xl'-F-Pcn*-Xlz-G-X6' -F-G-IDA-NMcI< -Y-P-C* 424 X1A-F-Pen*-X4At-G-X6D-X7AK-G-Sar-NMeEt-Y-P- C*

[0047] 425 X1A-F-Pen*-X4At-G-X6C-X7AL-G-IDA-NMeEt-Y- 426 X1A-F-Pen*-Et-G-X6C-X7AE-G-IDA-NMeKt-Y-P- P-C* C*

[0048] 427 Xl'-F-Pcn*-Xl' -G-X6'l-F-G-IDA-NMcE -Y-P- 428 R-F-Pen*-T-G-X6AM-F-G-Sar-NMeL-Y-P-C*

[0049] C*

[0050] 429 X1A-F-Pen*-X4At-G-X6AN-F-G-IDA-NMeEt-Y-P- 430 X1A-F-Pen*-X4At-G-X6C-X7AM-G-IDA-NMeEt-Y- C* P-C*

[0051] 431 Xl'-F-Pcn*-Xl' -G-X6' -X '-G-IDA-NMcE -Y-P- 432 X1A-F-Pen*-X4At-G-X6C-X7AN-G-IDA-NMeEt-Y- C* P-C*

[0052] 433 Xl''-F-Pcn*-Xl' -G-X6',,-F-G-IDA-NMcE -Y-P- 434 Kl-F-Pen*-X4At-G-X6C-F-G-Sar-NMeEt-Y-P-C*t C*

[0053] 435 Xl''-F-Pcn*-Xl' -G-X6'l'-F-G-IDA-NMcE -Y-P- 436 N-X2A-Pen*-Et-G-X6D-F-G-Sar-NMeKt-Y-P-C*

[0054] C*

[0055] 437 N-F-Pcn*-E -G-X6' -F-G-Sar-NMcI< -Y-P-C* 438 X1A-F-Pen*-X4At-G-X6C-X7AO-G-IDA-NMeEt-Y- P-C*

[0056] 439 R-F-Pen*-T-G-X6D-F-G-Sar-NMeL-Y-X12L-C* 440 R-F-Pen*-T-G-X6AQ-F-G-Sar-NMeL-Y-P-C* 441 Xl'-F-Pcn*-Xl' -G-X6'l<-F-G-IDA-NMcE -Y-P- 442 X1A-F-Pen*-X4At-G-X6C-X7H-G-Sar-NMeEt-Y-P- C* C*

[0057] 443 Xl'-F-Pcn*-Xl' -G-X6's-F-G-IDA-NMcE -Y-P- 444 X1A-F-Pen*-X4At-G-X6AT-F-G-IDA-NMeEt-Y-P- C* C*

[0058] 445 X1A-F-Pen*-X4At-G-X6C-X7B-G-IDA-NMeEt-Y-P- 446 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-X12M-C*

[0059] C*

[0060] 447 X1A-F-Pen*-X4At-G-X6C-X7AP-G-IDA-NMeEt-Y- 448 R-F-Pen*-T-G-X6AU-F-G-Sar-NMeL-Y-P-C*

[0061] P-C*

[0062] 449 X1A-F-Pen*-X4At-G-X6AV-F-G-IDA-NMeEt-Y-P- 450 X1A-F-Pen*-X4At-G-X6AE-F-G-IDA-NMeEt-Y-P- C* C*

[0063] 451 R-F-Pen*-T-G-X6AW-F-G-Sar-NMeL-Y-P-C* 452 X1A-F-Pen*-X4At-G-X®-X7AJ-G-Sar-NMeEt-Y-P- C*

[0064] 453 X1A-F-Pen*-X4At-G-X6C-X7AK-G-Sar-NMeEt-Y-P- 454 X1A-F-Pen*-X4At-G-X6AX-F-G-IDA-NMeEt-Y-P- C* C*

[0065] 455 X1A-F-Pen*-X4At-G-X6C-X7AQ-G-IDA-NMeEt-Y- 456 X1A-F-Pen*-X4At-G-X6AY-F-G-IDA-NMeEt-Y-P- P-C* C*

[0066] 457 Xl'-F-Pcn*-Xl' -G-X6'z-F-G-IDA-NMcE -Y-P- 458 X1A-F-Pen*-X4At-G-X®-X7AR-G-IDA-NMeEt-Y- C* P-C*

[0067] 459 R-F-Pen*-T-G-X®A-F-G-Sar-NMeL-Y-P-C* 460 X1A-F-Pen*-X4At-G-X6C-X7AS-G-IDA-NMeEt-Y- P-C*

[0068] 461 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-X12N-C* 462 X1A-F-Pen*-X4At-G-X6D-X7AT-G-IDA-NMeEt-Y-

[0069]

[0070] P-C* REF REF

[0071] ID Sequence ID Sequence

[0072] NO NO

[0073] 463 R-F-Pen*-T-G-X6BB-F-G-Sar-NMeL-Y-P-C* 464 X1A-F-Pen*-X4At-G-X6D-X7AU-G-IDA-NMeEt-Y- P-C*

[0074] 465 F-Pen*-T-G-H-F-G-X90-NMeL-Y-P-C* 466 R-F-Pcn*-E -G-XAI,-F-G-Sar-NMcI< -Y-P-C* 467 XI A-F-Pcn*-I< -G-X6' -F-G-Sar-NMcE -Y-P-C* 468 F-Pcn*-I< -G-EI-F-G-Sar-NMcE -Y-Xl 2,,-C* 469 R-F-Pen*-T-G-X®D-F-G-Sar-NMeL-Y-P-C* 470 K -F-Pcn*-Xll,-G-E[-F-G-Sar-NMcL-Y-P-C* 471 F-Pen*-T-G-H-F-G-X9R-NMeL-Y-P-C* 472 F-Pcn*-I< -G-EI-F-G-X9,s-NMcE -Y-P-C* 473 I< -F-Pcn*-T-G-H-F-G-X9s-NMcL-Y-P-C* 474 I< -F-Pcn*-T-G-H-F-G-X9l<-NMcL-Y-P-C* 475 F-Pen*-Et-G-H-F-G-Sar-NMeKt-Y-P-C* 476 R-X2E-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 477 N-F-Pcn*-I< -G-X6'-F-G-IDA-NMcE -Y-P-C* 478 D-F-Pcn*-K -G-E[-F-G-Sar-NMcE -Y-P-C* 479 XI A-F-Pcn*-E -G-E[-F-G-X9, |-NMcL-Y-P-C* 480 N-F-Pen*-Kt-G-H-F-G-IDA-NMeEt-Y-P-C* 481 F-Pcn*-I< -G-X6A-F-G-Sar-NMcE -Y-P-C* 482 XI A-F-Pcn*-I< -G-X6A-F-G-IDA-NMcE -Y-P-C* 483 XI A-F-Pcn*-I< -G-X6A-F-G-Sar-NMcE -Y-P-C* 484 XI A-F-Pcn*-I< -G-X6l,-F-G-Sar-NMcE -Y-P-C* 485 XI A-F-Pcn*-I< -G-E[-F-G-X9,|<-NMcE -Y-P-C* 486 N-F-Pcn*-E -G-EI-F-G-X9, |-NMcL-Y-P-C* 487 XI A-F-Pcn*-XIA-G-E[-F-G-Sar-NMcE -Y-P-C* 488 N-F-Pcn*-I< -G-X6A-F-G-Sar-NMcE -Y-P-C* 489 X1A-F-Pen*-X4At-G-H-F-G-roA-NMeEt-Y-P-C* 490 X1A-F-Pen*-X4At-G-H-F-G-X9At-NMeL-Y-P-C* 491 Kl-X2AA-Pen*-Kt-G-X-F-G-X9O-NMeEt-Y-P-C*t 492 XI A-F-Pcn*-I< -G-EI-F-G-IDA-NMcE -Y-P-C* 493 H-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 494 (D-His)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 495 N-F-Pcn*-XIA-G-EI-F-G-IDA-NMcE -Y-P-C* 496 X1A-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 497 N-F-Pcn*-K -G-E[-F-G-IDA-NMcI< -Y-P-C* 498 X1A-F-Pen*-Et-G-H-F-G-IDA-NMeKt-Y-P-C* 499 N-F-Pcn*-E -G-EI-F-G-IDA-NMcI< -Y-P-C* 500 R-F-Pen*-T-(D-Val)-H-F-G-Sar-NMeL-Y-P-C* 501 X1A-X2A-Pen*-X4At-G-X6C-F-G-Sar-NMeEt-Y-P- 502 N-X2A-Pen*-Et-G-X6C-F-G-Sar-NMeKt-Y-P-C*

[0075] C*

[0076] 503 X1A-F-Pen*-X4Bt-G-X®-F-G-IDA-NMeKt-Y-P- 504 X1A-F-Pen*-X4At-G-X6C-F-G-KDA-NMeEt-Y-P- C* C*

[0077] 505 N-X2A-Pen*-X4At-G-X®-F-G-Sar-NMeEt-Y-P-C* 506 N-X2A-Pen*-X4At-G-X6C-F-G-Sar-NMeEt-Y-P-C* 507 N-F-Pcn*-XIA-G-EI-F-G-Sar-NMcE -Y-P-C* 508 N-F-Pcn*-E -G-EI-F-G-Sar-XluA-Y-P-C* 509 R-F-Pen*-X4E-G-H-F-G-Sar-NMeL-Y-P-C* 510 R-F-Pen*-X4F-G-H-F-G-Sar-NMeL-Y-P-C* 511 R-F-Pen*-X4G-G-H-F-G-Sar-NMeL-Y-P-C* 512 Kl-F-Pen*-K-G-H-F-G-Sar-NMeL-Y-P-C*t 513 N-X2A-Pcn*-E -G-EI-F-G-Sar-NMcI< -Y-P-C* 514 F-Pcn*-I< -G-X6A-F-G-X9l<-NMcE -Y-P-C* 515 X1A-F-Pen*-X4At-G-X6BE-F-G-IDA-NMeEt-Y-P-

[0078]

[0079] C*

[0080] wherein:

[0081] Pen is penicillamine, Sar is sarcosine, NMeL is A'-mcthyl-lcucinc. NMeD is A'-mcthyl-aspartic acid, NMeE is A'-mcthyl-glutamic acid, NMeK is A'-mcthyl-lysinc. and IDA is iminodiacetic acid; andV1AV1B vlC lD 2AV2B 2C 2D 2EV2AAV4AV4B 4C 4D 4E 4F 4G 4Y 4Z 6AV6B A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., v6D -v6E -v6F v^G v6I v6K v6L v'GM v6N -v6P v6Q v^R v6S v6T -v6V -\r6W A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., -vx6X \x6Y \x6Z '\76AA y6AM v6AN v^AO A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., V^AP \x6AQ \x6AR v^AS -vASAT v^AU \x6AV \x6AW v^AX \x6AY v^AZ \x6BA -v^BB -VX6BC v^BD -v6BE v^ZA A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., V^ZB -v7A -v7B -\r7C v^D -v7E -v7F -\r7G -v7H '\7'7J yj-TK -v7L vTM -v7N -\r70 "v^P V^Q v^R v^S yrfT A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., ■V^U -v7V v7W -\7-7X -\r7AA v^AF A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A.,V7AMV7ANV7A0V7AP v7AQV7ARV7ASV7ATV7AUV7AVV9AV9BV9CV9DV9EV9FV9GV9HV9I A

[0082]

[0083] ., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A.,V9JV9KV9LV9MV9NV90V9PV9QV9RV9SV10AV11AV11BV11CV11DV12AV12BV12CV12DV12E A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., A., X12F, X12G, X12H, X121, X12J, X12K, X12L, X12M, X12N, and X120are as defined herein;

[0084] * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink;

[0085] t denotes crosslinked amino acids connected to each other via a crosslink; and

[0086] * denotes crosslinked amino acids connected to each other via a crosslink.

[0087] [7] In certain embodiments, the cyclic peptide may comprise a group of the formula: -L’-Rw. In certain embodiments, the cyclic peptide does not comprise a group of the formula: -L’-Rw. In certain embodiments, the cyclic peptide comprises a group of the formula: -L’-Rw.

[0088] [8] In certain embodiments, for example, a cyclic peptide disclosed herein is selected from those recited in Tables 2A-2B (infra), and pharmaceutically acceptable salts thereof.

[0089] [9] In certain embodiments, a cyclic peptide disclosed herein is selected from those recited in Table 2A (infra), and pharmaceutically acceptable salts thereof.

[0090]

[0010] Also provided herein are conjugates (“dimers” herein) comprising two cyclic peptides described herein, wherein the two cyclic peptides are conjugated to one another via a bond or a linker.

[0091]

[0011] In certain embodiments, neither, one, or both of the cyclic peptides of the dimer may comprise a group of the formula: -L’-Rw. In certain embodiments, neither of the cyclic peptides of the dimer comprises a group of the formula: -L’-Rw. In certain embodiments, exactly one cyclic peptide of the dimer comprises a group of the formula: -L’-Rw. In certain embodiments, both cyclic peptides of the dimer independently comprise a group of the formula: -L’-Rw.

[0092]

[0012] In certain embodiments, for example, a dimer disclosed herein is selected from those recited in Table 2B (infra), and pharmaceutically acceptable salts thereof.

[0093]

[0013] In another aspect, provided herein are pharmaceutical compositions comprising a cyclic peptide described herein, a dimer described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a cyclic peptide or dimer, or pharmaceutically acceptable salt thereof.

[0094]

[0014] As described, the cyclic peptides, dimers, and pharmaceutical compositions provided herein can non-covalently inhibit FcRn and are therefore useful for treating and / or preventing diseases, disorders, and conditions in a subject, including, e.g., indications in which FcRn activity and / or IgG antibodies are implicated.

[0095]

[0015] Provided herein are methods and uses of the cyclic peptides, dimers, and pharmaceutical compositions provided herein, including, but not limited to, the following:

[0096] (a) Methods of treating an FcRn-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0097] (b) Methods of treating an IgG-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0098] (c) Methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. (d) Methods of non-covalently inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0099] (e) Methods of decreasing IgG levels in a subject in need thereof comprising administering to the subject an effective amount of a cyclic peptide or dimer described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100]

[0016] Also provided herein cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in any of the foregoing (a)-(e). In another aspect, provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use as medicaments and / or for use in the manufacture of medicaments.

[0101]

[0017] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims.

[0102] DEFINITIONS

[0103] General Definitions

[0104]

[0018] The term “peptide” refers to a polymer of amino acid residues linked together by peptide bonds. Typically, a peptide will be at least three amino acids long, or at least the length required by an amino acid sequence provided herein. Peptides provided herein can include natural amino acids and / or unnatural amino acids (z. e., compounds that do not occur in nature but that can be incorporated into a peptide chain) in any combination. One or more of the amino acids in a peptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an isofamesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A peptide may be naturally occurring, recombinant, synthetic, or any combination of these.

[0105]

[0019] A peptide provided herein can be of any length. In certain embodiments, a peptide is 25 amino acids or fewer in length. In certain embodiments, a peptide is 20 amino acids or fewer in length. In certain embodiments, a peptide is 15 amino acids or fewer in length. In certain embodiments, a peptide is 13 amino acids or fewer in length. In certain embodiments, a peptide is 7-20 amino acids in length, inclusive. In certain embodiments, a peptide is 10-20 amino acids in length, inclusive. In certain embodiments, a peptide is 10-15 amino acids in length, inclusive. In certain embodiments, a peptide is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length. In certain embodiments, a peptide is at least the length of an amino acid sequence provided herein. In certain embodiments, a peptide is the length of an amino acid sequence provided herein.

[0106]

[0020] “Cyclic peptide” refers to a peptide in which two amino acids of the peptide (“crosslinked amino acids”) are connected via a crosslink to form a macrocycle. The crosslink may be attached any position on the crosslinked amino acids (e.g., attached independently to the a-sidechain, the a-carbon, or the peptide nitrogen of a crosslinked amino acid). For example, in certain embodiments, the a-sidechains of the crosslinked amino acids are connected to form the crosslink. In certain embodiments, the crosslink connects the a-carbons of the crosslinked amino acids. A cyclic peptide described herein may include more than one crosslink (e.g., two crosslinks, forming a bicyclic peptide).

[0107]

[0021] In certain embodiments, the crosslinked amino acids are separated by 5-13 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 6-12 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 7-11 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 8-10 amino acids, inclusive. In certain embodiments, the crosslinked amino acids are separated by 9 amino acids. In certain embodiments, the crosslinked amino acids are separated by 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acids.

[0108]

[0022] In certain embodiments, the crosslink is a bond, C O alkylene, C O haloalkylene, C O heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[0109]

[0023] In certain embodiments, the crosslink is a bond. In certain embodiments, the crosslink comprises optionally substituted CMO alkylene. In certain embodiments, the crosslink comprises optionally substituted CMO haloalkylene. In certain embodiments, the crosslink comprises optionally substituted Ci.

[0110] 10 heteroalkylene. In certain embodiments, the crosslink comprises optionally substituted CMO alkenylene. In certain embodiments, the crosslink comprises optionally substituted CMO heteroalkenylene. In certain embodiments, the crosslink comprises optionally substituted CMO alkynylene. In certain embodiments, the crosslink comprises optionally substituted CMO heteroalkynylene. In certain embodiments, the crosslink comprises optionally substituted C3-8 carbocyclylene. In certain embodiments, the crosslink comprises optionally substituted Cg-io arylene. In certain embodiments, the crosslink comprises optionally substituted 3-8 membered heterocyclylene. In certain embodiments, the crosslink comprises optionally substituted 5-10 membered heteroarylene.

[0111]

[0024] In certain embodiments, a-sidechains of the crosslinked amino acids are connected to form the crosslink. For example, in certain embodiments, a-sidechains of the crosslinked amino acids are — LC—

[0112] connected to form:a i a, wherein Lcis a crosslink; and each a represents attachment to the a-carbon of a crosslinked amino acid.

[0113]

[0025] For example, in certain embodiments, the crosslinked amino acids are penicillamine (Pen) anda

[0114] cysteine (C), and the crosslinked amino acids are connected to form:

[0115]

[0116] / \, wherein each a represents attachment to the a-carbon of a crosslinked amino acid.

[0117]

[0026] The term “amino acid” refers to a molecule containing both an amino group and a carboxyl group. Unless otherwise indicated, an amino acid is an alpha-amino acid (a-amino acid), the generic structure of which is depicted below (wherein each R is independently H or an amino acid sidechain, i. e., an “a- sidechain”). Unless otherwise indicated, reference to a particular amino acid implies the L-isomer of the amino acid. Each amino acid referred to herein may be denoted by a 1- to 4-letter code (e.g., R and Arg represent L-Arginine, NMeL represents N-methyl leucine, etc.).

[0118] R R OH

[0119] H2N a y

[0120] O

[0121] a- -amino acid

[0122]

[0027] Suitable amino acids include, without limitation, natural a-amino acids such as D- and L-isomers of the 20 common naturally occurring a-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided below), and unnatural a-amino acids.

[0123]

[0028] Exemplary natural a-amino acids (with one-letter code provided in parentheses) include L-alanine (A), L-arginine (R), L-asparagine (N), L-aspartic acid (D), L-cysteine (C), L-glutamic acid (E), L-glutamine (Q), glycine (G), L-histidine (H), L-isoleucine (I), L-leucine (L), L-lysine (K), L-methionine (M), L-phenylalanine (F), L-proline (P), L-serine (S), L-threonine (T), L-tryptophan (W), L-tyrosine (Y), and L- valine (V).

[0124]

[0029] Exemplary unnatural a-amino acids include, without limitation, D-arginine, D-asparagine, D-aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, D-valine, Di-vinyl, a-methyl-alanine (Aib), a-methyl-arginine, a-methyl-asparagine, a-methyl-aspartic acid, a-methyl-cysteine, a-methyl-glutamic acid, a-methyl-glutamine, a-methyl-histidine, a-methyl-isoleucine, a-methyl-leucine, a-methyl-lysine, a-methyl-methionine, a-methyl-phenylalanine, a-methyl-proline, a-methyl-serine, a-methyl-threonine, a-methyl-tryptophan, a-methyl-tyrosine, a-methyl-valine, norleucine, and terminally unsaturated a-amino acids. There are many known unnatural amino acids, any of which may be included in the peptides of the present disclosure. See for example, S. Hunt, The Non- -Protein Amino Acids: In Chemistry and Biochemistry of the Amino Acids, edited by G. C. Barrett, Chapman and Hall, 1985.

[0125]

[0030] Unnatural amino acids also include amino acids comprising a substituent (z. e., non-hydrogen group) on the peptide nitrogen. For example, any amino acid described herein can comprise a Ci-6 alkyl group on the peptide nitrogen (“N-alkyl”-amino acid). In certain embodiments, any amino acid described herein can comprise a methyl group on the peptide nitrogen (“N-methyl”-amino acid). For example, “N-methyl-leucine” refers to L-leucine wherein the peptide nitrogen is substituted with methyl.

[0126]

[0031] Non-limiting examples of unnatural amino acids referenced in the disclosure are provided in Table 1A. In certain embodiments, the unnatural amino acid is selected from those in Table 1A, and D-isomers thereof.

[0127] Table 1A

[0128] Name Abbreviation Structure Sarcosine (N-methyl glycine) SarHN-Y0H

[0129]

[0130] N-methyl leucine NMeL H / YOH

[0131] 10

[0132] -AXSH Penicillamine Pen

[0133] H2N^Y0H

[0134]

[0135] 0

[0136]

[0032] In certain embodiments, the unnatural amino acid is a phenylalanine replacement. “Phenylalanine replacement” refers to amino acid of Formula (a), an amino acid provided in Table IB below, or any other phenylalanine replacement described herein. In certain embodiments, a phenylalanine replacement is of Formula (a):

[0137]

[0138] 0(a),

[0139] or a D-isomer thereof, wherein:

[0140] m is 1, 2, 3, or 4;

[0141] each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0142] each R2is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, -CN, -NO2, -ORA, -C1-6 alkyl-ORA, -N(RA)2, -SRA, -C(=O)RA, -C(=O)ORA, -C(=0)N(RA)2, -S(=O)RA, -S(=O)2RA, -S(=O)2ORB-S(=O)2N(RB)2, C3-8carbocyclyl, C 6-10 aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl; each instance of RAis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C(=O)RB, -S(=O)2RB, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RAattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl;

[0143] each RBis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl;

[0144] R3is hydrogen or C1-6 alkyl; and

[0145] n is 0, 1, 2, 3, 4 or 5.

[0146]

[0033] In certain embodiments, a phenylalanine replacement is of the formula:

[0147]

[0148] O, or a D-isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -OCF3, -SO2Me, -SO3H, -NO2, -CN, -Ph, or -CH2-(C6- 10 aryl). R2

[0149]

[0034] In certain embodiments, a phenylalanine replacement is of the formula:

[0150]

[0151] O, or a D-isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -OCF3, -SChMe, -SO3H, -NO2, -CN, -Ph, or -CH2-(C6- 10 aryl).

[0152]

[0035] In certain embodiments, a phenylalanine replacement is of the formula:

[0153]

[0154] O, or a D-isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -OCF3, -SO2Me, -SO3H, -NO2, -CN, -Ph, or -CH2- (C6- 10 aryl).

[0155]

[0036] In certain embodiments, a phenylalanine replacement is an amino acid provided in Table IB, or a D-isomer thereof.

[0156] Table IB

[0157]

[0158]

[0159] Phenylalanine Replacements

[0160] H2N'V°HH2N^ H2N^ H2N^

[0161] 0 0 0 o

[0162] H2N'\0HH2N^Y0HH2N^^ 0 0 0 0

[0163] A^o

[0164] H2AY°HH2N\OHH2N-VOHH2N\ 00H

[0165] 0 0 o o-^

[0166] N S N

[0167] H2AY°HH2N\OHH2N-YOHH2N\OH0 o o o Al,s. H 'N Nx

[0168] AO

[0169] H2N'\OHH2AY°HH2AYOH

[0170] - H2AY0H0 0 0

[0171] < 0

[0172] N I^N \

[0173] JL ij

[0174] z ry^N'

[0175] H2NVHHA0H0 0 0

[0176] \

[0177] X u. xy^N~ JOL jO f 's

[0178] H2AY°HH H2N-VOH0 AY0H

[0179] 0 o cr " OH OH JO vjO -... A) H2NA H2N^YOHHA “ CT ’OH H2NV 0 0

[0180]

[0181] 0 Phenylalanine Replacements

[0182] OH H H H N N N

[0183] " AO AO H2N'VOHH2N-*YOHH2N<^0HH2Ay0H

[0184] 0 0 0 0

[0185] H H JL# y-OH CO

[0186] T K> 1 °\

[0187] H2N\OHz H2NVHH. N4OHH2NC0H

[0188] 0 o. 0 0

[0189] 0

[0190] / < > o (=— H y° o «- N

[0191] \ / T _

[0192] o

[0193] AO

[0194] H2NC " H. N^ n HsN^ y^01"1 / ° 0 0 0

[0195] 1 0

[0196] Yj

[0197] H2N\OHH2N\OHH^ / YOH

[0198] 0 \ I 0

[0199] o o 0

[0200] A 4 os Tj A^AQH

[0201] H2N\

[0202] zOHH2NJY0HH2N^YOHH2IO0HN C

[0203] I 0 0 0 0

[0204] - - - H2N^VH

[0205]

[0206] 0

[0207]

[0037] In certain embodiments, the unnatural amino acid is a tyrosine replacement. “Tyrosine replacement” refers to amino acid of Formula (a) (e.g., Formula (b)), an amino acid provided in Table 1C below, or any other tyrosine replacement described herein. In certain embodiments, a tyrosine replacement is of Formula (b):

[0208]

[0209] or a D-isomer thereof, wherein: each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl; and

[0210] RAis Ci.6 alkyl or Ci-6 haloalkyl.

[0211]

[0038] In certain embodiments, a tyrosine replacement is of the formula:

[0212]

[0213] O, or a D-isomer thereof, wherein R2is F, Cl, Br, methyl, -OMe, -NO2, -NH2, -CN, -CO2H, -OCF3, -CHF2, -CF3, -N(Me)2, -NHC(0)Me, -SO2Me, -SO3H, -SMe, -NHS02Me, -SO2NH2, or -CH20H.

[0214] R2

[0215]

[0039] In certain embodiments, a tyrosine replacement is of the formula:

[0216]

[0217] O, or a D-isomer thereof, wherein R2is -OH, F, Cl, Br, methyl, -CF3, -OMe, -NH2, -NO2, -CN, -CH2OH, -CO2H, -S(O)Me, or -C(0)NH2.

[0218]

[0040] In certain embodiments, a tyrosine replacement is an amino acid provided in Table 1C, or a D-isomer thereof.

[0219]

[0220]

[0221] Tyrosine Replacements

[0222] rj

[0223] - - H2N\OHH2N^0H

[0224] 0 0

[0225]

[0226]

[0041] In certain embodiments, the unnatural amino acid is a histidine replacement. “Histidine replacement” refers to amino acid of Formula (c-l),(c-2), (c-3), or (c-4), an amino acid provided in Table ID below, or any other histidine replacement described herein. In certain embodiments, a histidine replacement is of Formula (c-1) or (c-2):

[0227]

[0228] or a D-isomer thereof, wherein:

[0229] m is 1, 2, 3, or 4;

[0230] each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0231] R3is hydrogen or Ci-6 alkyl; and

[0232] RNis hydrogen or Ci-6 alkyl.

[0233] In certain embodiments, a histidine replacement is of Formula (c-1), or a D-isomer thereof. In certain embodiments, a histidine replacement is of Formula (c-2), or a D-isomer thereof.

[0234]

[0042] In certain embodiments, the histidine replacement comprises a pyridine ring. In certain embodiments, the histidine replacement is of Formula (c-3):

[0235]

[0236] 0(c-3),

[0237] or a D-isomer thereof, wherein:

[0238] m is 1, 2, 3, or 4;

[0239] each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0240] R3is hydrogen or Ci-6 alkyl; and

[0241] P is optionally substituted pyridyl;

[0242]

[0043] In certain embodiments, a histidine replacement is of Formula (c-3):

[0243]

[0244] O (c-3),

[0245] or a D-isomer thereof, wherein:

[0246] m is 1, 2, 3, or 4;

[0247] each R1is independently hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0248] R3is hydrogen or Ci-6 alkyl; and

[0249] Rclis hydrogen, halogen, Ci-6 alkyl, or Ci-6 haloalkyl; and

[0250] Rc2is -ORAor -N(RA)2;

[0251] each instance of RAis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Cg-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RAattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl, wherein each alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl is optionally substituted.

[0252]

[0044] In certain embodiments, a histidine replacement is an amino acid provided in Table ID, or a D-isomer thereof.

[0253] Table ID

[0254] Histidine Replacements

[0255] N==\ N==\

[0256] J^ / N

[0257] H2N\OHH2N\OHH2N\OH0 H2NVH

[0258] 0 0 0 HN"\\ HN-N HN-N HN-^

[0259] H2N\OHH2N-\OHH2N\OHH2N\OH0 0 0 0

[0260] s-^

[0261] NH

[0262] ! ^N /

[0263] H2N\OHH2N\OHH2N\OHH2N'V> H0 0 0 0 N^=\ N=\

[0264] L, NH

[0265] fN^N^0NHH2N^OHH2N\OHH2 / YOH

[0266] 0 0 0 H2NVH

[0267]

[0268] 0 Histidine Replacements

[0269] / 0

[0270] N-N HN- \

[0271] JI 'N<zNH HN'^T^ o

[0272] H. N^ n H2N^YOHH2NV H2N^YOH0 0 0

[0273] 0

[0274] o XN N

[0275] JL JJ rj

[0276] H2N\OHH H2 2N\ N\OH OH

[0277] 0 0

[0278] o

[0279] N^N

[0280] n

[0281] >^N AA jLx rrF

[0282] H2N\OHH2N\OH

[0283] H2NVH

[0284] 0 0 0 H2NY 0OH_^\, NH2H H N nr I T Y

[0285] A / NH Tj

[0286] H2N\OHH2NYOHH2N^Y HA 0OH™ 0 0 0 X" NH °y^H2HN^NHs NH2

[0287] I Iix NH z

[0288] H2N\-OHH2N-H

[0289] 0

[0290] H2NY0HH2NXY o=\°H0

[0291] 0 O> \ o \ / 1_ NH HN^NH2 NH2NH X2

[0292] HN NH2NH

[0293] H2N^YOHH2N-YH

[0294] o H2X0H

[0295] 0

[0296] 0 HYY0OHNH NH2

[0297] HN^NH2MeCk ^\_ /

[0298] A \^- INI I T il

[0299] HYHH2NY°HH2N\0Ho H2N^YOH0 0

[0300]

[0301] 0 Histidine Replacements

[0302] 1 f^NH H2Nxx>. 1 <\\ o^ xN^x^\xV z T H °\x X T H Yr o / J\ A^N T ii

[0303] A / N / AY / N I 11

[0304] ^> Mo / Az^ L<z°'Z“NH2N-YOHnYy0" H2N\OHz z

[0305] 0 0 0 H2NA0H0 \ xO. / ^ / H

[0306] 1 1 II T T H / A / N ft zA / NXA^N o OL

[0307] H2rZY0HHZY°HH2NV o A / -H

[0308] 0 z \ H2NY0H0 i cx 0 0 0 H

[0309] N=\

[0310] L^SY'NN^

[0311] L N-S'° ^ / AAN

[0312] H, N\OHA b H2N\ H2NH00HV

[0313] 0 0 0

[0314] H

[0315] . N

[0316] \ II

[0317] AAXNrr 5— XA— OH

[0318] A ™ H2N4OHH2N\OH

[0319] 0 0 0

[0320] NC^N

[0321] Tj

[0322] H2NV H, N\CIH

[0323] 0 0

[0324] N-NH H X) H

[0325] r N. ZNKi n p ii AA / AtxN

[0326] \ 'N==ft

[0327] H2NYOHH2NJY°H° H2N-VOHH2NVH0 0 0 0

[0328] \l"^ s-Y L N ^°Y^ii

[0329] xft / N / A^N JA"NH2N^YOHH2LYOHH. N^ n HA0H0 0 0 0 N V YX / F 1

[0330] 1 II o^xA T ii AAQ / A^N /

[0331] / A \ ^ 11 A^X NN

[0332] 2xL / OH 1

[0333] H N Y H2-^YC'H

[0334] 0 0 H2N-\OHH. N'Y™

[0335] 0

[0336]

[0337] 0

[0338]

[0339]

[0045] In certain embodiments, the unnatural amino acid is a proline replacement. “Proline replacement” refers to an amino acid of Formula (d), or any other proline replacement described herein:

[0340]

[0341] or a D-isomer thereof, wherein:

[0342] pl is 0, 1, 2, or 3;

[0343] each R4is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, -CN, -ORA, -N(RA)2, -SRA, -C(=O)RA, -C(=O)ORA, -C(=O)N(RA)2, C3-8 carbocyclyl, Cg-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two R4attached to the same carbon atom are joined together with the intervening atoms to form C3-8 carbocyclyl or 3-8 membered heterocyclyl, or two R4are taken together to form =0; and

[0344] each instance of RAis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Cg-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RAattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; and

[0345] p2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits. *

[0346]

[0046] In certain embodiments, a proline replacement is an amino acid provided in Table IE, o / r°- a D-isomer _ O ZI

[0347] thereof.

[0348] Table IE

[0349] Proline Replacements

[0350] H2NZ, 0 HjM^ - O

[0351] L'" N OH N OH

[0352] HHOH OH O^ OH

[0353] O

[0354] / 0H

[0355] HOHHJHHH OH HO.0HO0

[0356] ryw Cr°rw

[0357] N OH H OH OH N OH H H

[0358] Cl 0 / °

[0359] / ° - H OH N OH N OH

[0360]

[0361]

[0047] In certain embodiments, the unnatural amino acid is a cysteine replacement. “Cysteine replacement” refers to an amino acid of Formula (e), or any other cysteine replacement described herein:

[0362]

[0363] O

[0364] or a D-isomer thereof, wherein:

[0365] m is 1, 2, 3, or 4;

[0366] each R1is independently hydrogen, Ci-6 alkyl, or Ci-ehaloalkyl;

[0367] R3is hydrogen or Ci-6 alkyl; and

[0368] Rsis hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0369]

[0048] In certain embodiments, the unnatural amino acid is a threonine or serine replacement. “Threonine replacement” and “serine replacement” independently refer to an amino acid of Formula (f), or any other threonine replacement described herein: R°

[0370]

[0371] 0(f),

[0372] or a D-isomer thereof, wherein:

[0373] m is 1, 2, 3, or 4;

[0374] each R1is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0375] R3is hydrogen or Ci-6 alkyl; and

[0376] R° is hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0377]

[0049] In certain embodiments, the unnatural amino acid is a glycine replacement. “Glycine replacement” refers to an amino acid of Formula (g), or any other glycine replacement described herein:

[0378]

[0379] 0(g),

[0380] or a D-isomer thereof, wherein:

[0381] each R3is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl.

[0382]

[0050] In certain embodiments, the unnatural amino acid is a lysine replacement. “Lysine replacement” refers to an amino acid of Formula (h-1) or (h-2), or any other lysine replacement described herein:

[0383]

[0384] or a D-isomer thereof, wherein:

[0385] m is 1, 2, 3, or 4;

[0386] each R1is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl;

[0387] R3is hydrogen or C1-6 alkyl;

[0388] each instance of RNis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C(=O)RB, -S(=O)2RB, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RNattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; and

[0389] each RBis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[0390] In certain embodiments, “lysine replacement” refers to an amino acid of Formula (h-1), or a D-isomer thereof. In certain embodiments, “lysine replacement” refers to an amino acid of Formula (h-2), or a D-isomer thereof.

[0391]

[0051] In certain embodiments, a lysine replacement is an amino acid provided in Table IF, or a D-isomer thereof.

[0392]

[0393]

[0052] In certain embodiments, the unnatural amino acid is a sarcosine replacement. “Sarcosine replacement” refers to an amino acid of Formula (j), or any other sarcosine replacement described herein:

[0394] R3R3

[0395]

[0396] or a D-isomer thereof, wherein:

[0397] each R3is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[0398] R5is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=0)Rc, or -S(=O)2RC, or a group selected from polymers, lipids, and fatty acids; and

[0399] each Rcis independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or a group selected from a group selected from polymers, lipids, and fatty acids.

[0053] In certain embodiments, a sarcosine replacement is an amino acid provided in Table 1G, or a D-isomer thereof.

[0400] Table 1G

[0401] Sarcosine Replacements

[0402] 0

[0403] HOY^ ° o0 HNA> H

[0404] OH OH OH

[0405] o^1^^ 0 0 o^-'" 0HN^OHHN^OH OH OH IZ OH OH OH I J

[0406] 0 o^ y o 0

[0407] o

[0408] "'AHN-A>H™AJHQH 0

[0409] H

[0410] F3C'^I IZ

[0411] 0 HO^^^i 0

[0412] °=< Y 1 flHN'-\> HHNA h° * H O-NHN-A)H H FL H flXf'O^A'N^x73H o

[0413] 'z2 I 'z4

[0414] H 'z3 A -HAOHT NH Iuo o

[0415] 0 0 0

[0416] HO. / x.,,, O^OH

[0417] NH Iu u0 0

[0418]

[0419] O 0 0

[0420]

[0054] In certain embodiments of Formula (j), each R3is hydrogen.

[0421]

[0055] The term “amino acid substitution” when used in reference to an amino acid sequence refers to an amino acid of the amino acid sequence being replaced by a different amino acid (e.g., replaced by a natural or unnatural amino acid described herein). An amino acid sequence provided herein may include one or more amino acid substitutions. In certain embodiments, an amino acid sequence provided herein includes 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 amino acid substitutions.

[0422]

[0056] The term “amino acid addition” when used in reference to an amino acid sequence refers to an amino acid (e.g., a natural or unnatural amino acid described herein) being inserted between two amino acids of the amino acid sequence, or added at either end of the sequence. In certain embodiments, an amino acid sequence herein includes 0, 1, 2, 3, 4, or 5 amino acid additions.

[0423]

[0057] The term “amino acid deletion” when used in reference to an amino acid sequence refers to an amino acid of the amino acid sequence being deleted from the amino acid sequence. In certain embodiments, an amino acid sequence herein includes 0, 1, 2, 3, 4, or 5 amino acid deletions.

[0424]

[0058] A cyclic peptide provided herein can comprise one or more additional modifications. For example, in certain embodiments, the N-terminus of the cyclic peptide is acylated (denoted by “Ac-” at the N-terminus of an amino acid sequence). In certain embodiments, the C-terminus of the cyclic peptide is amidated, i. e., the traditional C-terminal -C(=O)OH is replaced with -C(=O)NH2 (denoted by “-NH2” at the C-terminus of an amino acid sequence) or -C(=O)NH- (denoted by “-NH-” at the C-terminus of an amino acid sequence). In certain embodiments, a cyclic peptide provided herein comprises an acylated N-terminus and an amidated C-terminus.

[0425]

[0059] Throughout the present disclosure, references to “the peptide,” “a peptide,” “the cyclic peptide,” or “a cyclic peptide” provided herein are intended to encompass peptides comprising any amino acid sequence provided herein (including any disclosed amino acid substitutions, additions, deletions, and / or modifications), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof as described herein.

[0426] Likewise, references to “a dimer,” “the dimer,” and the like, are intended to encompass any dimers provided herein, and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof as described herein.

[0427]

[0060] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the peptides of this invention include those derived from inorganic and organic acids and bases.

[0428]

[0061] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in Pharmaceutical Sciences, \9T1, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the peptides of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0429] Chemical Definitions

[0430]

[0062] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, Marchs ’ A dvance d Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0431]

[0063] Peptides and amino acids described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the peptides described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses peptides as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0432]

[0064] Unless otherwise provided, the disclosure includes peptides that do not include isotopically enriched atoms, and also includes peptides that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, peptides having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C -enriched carbon are within the scope of the disclosure. Such peptides are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0433]

[0065] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “Ci-6alkyl” encompasses, Ci, C2, C3, C4, C5, C6, Ci-6, C1-5, Ci^, C1-3, C1-2, C2C2-5, C24. C2-3, C3-6, C3-5, C34. C4... C4-5, and Cs., alkyl.

[0434]

[0066] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0435]

[0067] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0436]

[0068] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0437]

[0069] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., w-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., w-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert-amyl), and hexyl (Ce) (e.g., w-hexyl). Additional examples of alkyl groups include w-heptyl (C7), w-octyl (Cs), w-dodecyl (Ci2), and the like.

[0438]

[0070] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“Ci_2o haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCI3, -CFC12, -CF2C1, and the like.

[0439]

[0071] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroCi-2o alkyl”).

[0440]

[0072] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3or ) may be in the (E)- or (^-configuration.

[0441]

[0442]

[0073] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkenyl”).

[0443]

[0074] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).

[0444]

[0075] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroCi-20 alkynyl”).

[0445]

[0076] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0446]

[0077] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0447]

[0078] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0448]

[0079] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.

[0449] “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom or the ring that does not contain a heteroatom.

[0450]

[0080] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0451]

[0081] A chemical moiety is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, acyl groups are optionally substituted. In general, the term “substituted” when referring to a chemical group means that at least one hydrogen present on the group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The invention is not limited in any manner by the exemplary substituents described herein.

[0452]

[0082] Exemplary substituents include, but are not limited to, halogen, -CN, -NO2, “Ns, -SO2H, -SO3H, -OH, -ORaa, -0N(Rbb)2, -N(Rbb)2, -N(Rbb)3+X, -N(0Rcc)Rbb, -SH, -SRaa, -SCN, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(0RCC)2, -C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)0Raa, -0C(=NRbb)Raa, -0C(=NRbb)0Raa, -C(=NRbb)N(Rbb)2, -0C(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, — Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, -NRbbP(=0)(Raa)2, -NRbbP(=0)(0Rcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X, -P(ORCC)3+X, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -0P(RCC)3+X, -OP(ORCC)2, -0P(0RCC)3X, -OP(RCC)4, -OP(ORcc)4,-B(Raa)2, -B(0RCC)2, -BRaa(0Rcc), Ci-2o alkyl, Ci_2o perhaloalkyl, Ci_2o alkenyl, Ci_2o alkynyl, hctcroCj _20alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl; wherein X is a counterion;

[0453] or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=0)2Raa, =NRbb, or =N0Rcc; wherein:

[0454] each instance of Raais, independently, selected from Ci_2o alkyl, Ci_2o perhaloalkyl, Ci_2o alkenyl, Ci-2o alkynyl, heteroCi-2o alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring;

[0455] each instance of Rbbis, independently, selected from hydrogen, -OH, -0Raa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(RCC)2, -C02Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=0)(Raa)2, -P(=0)(0RCC)2, -P(=O)(N(RCC)2)2, CI-20 alkyl, Ci-2o perhaloalkyl, Ci-2o alkenyl, Ci-2o alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring;

[0456] each instance of Rccis, independently, selected from hydrogen, C1-20 alkyl, C1-20 perhaloalkyl, Ci- 20 alkenyl, C1-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each X is a counterion.

[0457]

[0083] In certain embodiments, each substituent is independently halogen, substituted (e.g, substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -SCN, -NO2, -N3, -C(=0)Raa, -C02Raa, -C(=0)N(Rbb)2, -0C(=0)Raa, -0C02Raa, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, or -NRbbC(=0)N(Rbb)2.

[0458]

[0084] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F, Cl”, Br ", I"), NO3. CIO4”, OH", H2PO4 ", HCO3, HSO4 ", sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluene sulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4, PF4, PF6, AsF6, SbF6", B[3,5-(CF3)2C6H3]4]", B(CeF5)4, BPh4", A1(OC(CF3)3)4 ”, and carborane anions (e.g., CB11H12” or (HCBnMesBre) ). Exemplary counterions which may be multivalent include CO32, HPO42”, PO43”, B O?2, SO42”, S2O32, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0459]

[0085] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not limited in any manner by the above exemplary listing of substituents.

[0460] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0461]

[0086] Provided herein are cyclic peptides capable of binding to and inhibiting neonatal fragment crystallizable receptor (FcRn) proteins, dimers thereof, and pharmaceutical compositions thereof, and methods of using the same for treating and / or preventing diseases and conditions associated with FcRn activity in a subject, including diseases and conditions associated with immunoglobulin G (IgG) autoantibody levels (e.g., autoimmune diseases, inflammatory diseases). In some embodiments, cyclic peptides (and dimers thereof) described herein do not induce a histamine response in subject, or induce a reduced histamine response in a subject compared with other cyclic peptide inhibitors of FcRn.

[0462] Cyclic Peptides

[0463] Amino Acid Sequences of REF ID NO: 1

[0464]

[0087] In one aspect, provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising the amino acid sequence:

[0465] X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(REF ID NO: 1), wherein:

[0466] XIis arginine (R), D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[0467] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[0468] X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via an X3-X13crosslink;

[0469] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), D-glutamic acid (D-Glu), or other amino acid;

[0470] X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid, or is absent;

[0471] X6is histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;

[0472] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;

[0473] X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[0474] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid;

[0475] X10is -methyl-leucine (NMeL), D--methyl-leucine (D-NMeL), -methyl-aspartic acid (NMeD), D--methyl-aspartic acid (D-NMeD), -methyl-glutamic acid (NMeE), D--methyl-glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), -methyl-lysine (NMeK), D--methyl-lysine (D-NMeK), lysine (K), D-lysine (D-Lys), or other amino acid;

[0476] X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; and

[0477] X12is proline (P), D-proline (D-Pro), or a proline replacement;

[0478] optionally wherein:

[0479] X1and X13are crosslinked amino acids connected via an X’-X13crosslink; and / or

[0480] X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink;

[0481] provided that:

[0482] X1is not R and is not absent; and / or

[0483] X2is not F; and / or

[0484] X3is not Pen; and / or

[0485] X5is not G; and / or

[0486] X9is not Sar; and / or

[0487] X10is not NMeL; and / or

[0488] X13is not C; and / or

[0489] X1and X13are crosslinked amino acids connected via an X’-X13crosslink; and / or

[0490] X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

[0491]

[0088] In certain embodiments, X1is not R and is not absent.

[0492]

[0089] In certain embodiments, X2is not F.

[0493]

[0090] In certain embodiments, X3is not Pen.

[0494]

[0091] In certain embodiments, X5is not G.

[0495]

[0092] In certain embodiments, X9is not Sar.

[0496]

[0093] In certain embodiments, X10is not NMeL.

[0497]

[0094] In certain embodiments, X13is not C.

[0498]

[0095] In certain embodiments, a-sidechains of X3and X13are connected to form the X3-X13crosslink.

[0499]

[0096] In certain embodiments, the X3-X13crosslink connects the a-carbons of X3and X13.

[0500]

[0097] In certain embodiments of REF ID NO: 1,

[0501] X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[0502] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;

[0503] X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via an X3-X13crosslink;

[0504] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid;

[0505] X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid, or is absent;

[0506] X6is histidine (H), D-histidine (D-His), or a histidine replacement;

[0507] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent; X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[0508] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid;

[0509] X10is A-methyl -leucine (NMeL), D-A-methyl-leucine (D-NMeL), '-mcthy I -aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), D- '-mcthyl- glutamic acid (D-NMeE), or other amino acid;

[0510] X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; and

[0511] X12is proline (P), D-proline (D-Pro), or a proline replacement;

[0512]

[0098] In certain embodiments of REF ID NO: 1,

[0513] XIis arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent;

[0514] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;

[0515] X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), or a cysteine replacement;

[0516] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;

[0517] X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile), or is absent;

[0518] X6is histidine (H), D-histidine (D-His), or a histidine replacement;

[0519] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;

[0520] X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[0521] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[0522] X10is A-methyl -leucine (NMeL), D-A-methyl-leucine (D-NMeL), A-methyl -aspartic acid (NMeD), D-A-methyl-aspartic acid (D-NMeD), A-methyl-glutamic acid (NMeE), or D-A-methyl-glutamic acid (D-NMeE);

[0523] X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; and X12is proline (P), D-proline (D-Pro), or a proline replacement.

[0524]

[0099] In certain embodiments of REF ID NO: 1,

[0525] X1is arginine (R), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent;

[0526] X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;

[0527] X3and X13are each independently penicillamine (Pen), cysteine (C), or a cysteine replacement; X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement;

[0528] X5is glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I), or is absent;

[0529] X6is histidine (H) or a histidine replacement;

[0530] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;

[0531] X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I);

[0532] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I);

[0533] X10is N-methyl-leucine (NMeL), N-methyl-aspartic acid (NMeD), or N-methyl-glutamic acid (NMeE);

[0534] X11is tyrosine (Y), a tyrosine replacement, phenylalanine (F), or a phenylalanine replacement; and

[0535] X12is proline (P) or a proline replacement.

[0536]

[0100] In certain embodiments, X1is arginine (R), D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), aspartic acid (D), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), asparagine (N), or leucine (L), or is absent.

[0537]

[0101] In certain embodiments, X1is arginine (R). In certain embodiments, X1is D-arginine (D-Arg). In certain embodiments, X1is aspartic acid (D). In certain embodiments, X1is D-aspartic acid (D-Asp). In certain embodiments, X1is asparagine (N). In certain embodiments, X1is D-asparagine (D-Asn). In certain embodiments, X1is glutamine (Q). In certain embodiments, X1is D-glutamine (D-Gln). In certain embodiments, X1is leucine (L). In certain embodiments, X1is D-leucine (D-Leu). In certain embodiments, X1is lysine (K). In certain embodiments, X1is D-lysine (Lys). In certain embodiments, X1 is a lysine replacement. In certain embodiments, X1is another amino acid. In certain embodiments, X1is absent.

[0538]

[0102] In certain embodiments, X1is a lysine replacement selected from:

[0539]

[0540] O

[0541]

[0542]

[0103] In certain embodiments, X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), a tyrosine replacement, histidine (H), a histidine replacement, lysine (K), or a lysine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), or is absent.

[0543]

[0104] In certain embodiments, X2is phenylalanine (F). In certain embodiments, X2is D-phenylalanine (D-Phe). In certain embodiments, X2is a phenylalanine replacement. In certain embodiments, X2is tyrosine (Y). In certain embodiments, X2is D-tyrosine (D-Tyr). In certain embodiments, X2is a tyrosine replacement. In certain embodiments, X2is histidine (H). In certain embodiments, X2is D-histidine (D- His). In certain embodiments, X2is a histidine replacement. In certain embodiments, X2is lysine (K). In certain embodiments, X2is D-lysine (Lys). In certain embodiments, X2is a lysine replacement.

[0544]

[0105] In certain embodiments, X2is another amino acid. In certain embodiments, X2is absent.

[0106] In certain embodiments, X2is a phenylalanine replacement selected from:

[0545]

[0546] O

[0547]

[0548]

[0107] In certain embodiments, X3is penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), or a cysteine replacement. In certain embodiments, X3is penicillamine (Pen), cysteine (C), or a cysteine replacement.

[0549]

[0108] In certain embodiments, X3is penicillamine (Pen). In certain embodiments, X3is D-penicillamine (D-Pen). In certain embodiments, X3is cysteine (C). In certain embodiments, X3is D-cysteine (D-Cys). In certain embodiments, X3is a cysteine replacement. In certain embodiments, X3is another amino acid.

[0550]

[0109] In certain embodiments, X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D -serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), or D-glutamic acid (D-Glu). In certain embodiments, X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), a lysine replacement, aspartic acid (D), or glutamic acid (E). In certain embodiments, X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement. In certain embodiments, X4is threonine (T) or lysine (K).

[0110] In certain embodiments, X4is threonine (T). In certain embodiments, X4is D-threonine (D-Thr). In certain embodiments, X4is a threonine replacement. In certain embodiments, X4is serine (S). In certain embodiments, X4is D-serine (D-Ser). In certain embodiments, X4is a serine replacement. In certain embodiments, X4is lysine (K). In certain embodiments, X4is D-lysine (Lys). In certain embodiments, X4is a lysine replacement. In certain embodiments, X4is aspartic acid (D). In certain embodiments, X4is D-aspartic acid (D-Asp). In certain embodiments, X4is glutamic acid (E). In certain embodiments, X4is D-glutamic acid (D-Glu). In certain embodiments, X4is another amino acid.

[0551] NH2H2N [Hl] In certain embodiments, X4is a lysine replacement selected from:

[0552]

[0553] o

[0554]

[0555] replacement that is

[0556]

[0112] In certain embodiments, X4is another amino acid that i

[0557]

[0558] s O. In certain embodiments, O

[0559] X4is another amino acid that is

[0560]

[0561] O

[0562]

[0113] In certain embodiments, X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile), or is absent. In certain embodiments, X5is glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I), or is absent.

[0563]

[0114] In certain embodiments, X5is glycine (G). In certain embodiments, X5is a glycine replacement. In certain embodiments, X5is alanine (A). In certain embodiments, X5is D-alanine (D-Ala). In certain embodiments, X5is valine (V). In certain embodiments, X5is D-valine (D-Val). In certain embodiments, X5is leucine (L). In certain embodiments, X5is D-leucine (D-Leu). In certain embodiments, X5is isoleucine (I). In certain embodiments, X5is D-isoleucine (D-Ile). In certain embodiments, X5is another amino acid. In certain embodiments, X5is absent.

[0564]

[0115] In certain embodiments, X6is histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, X6is histidine (H), D-histidine (D-His), or a histidine replacement. In certain embodiments, X6is histidine (H), a histidine replacement, lysine (K), or a lysine replacement. In certain embodiments, X6is histidine (H) or a histidine replacement.

[0565]

[0116] In certain embodiments, X6is histidine (H). In certain embodiments, X6is D-histidine (D-His). In certain embodiments, X6is a histidine replacement. In certain embodiments, X6is lysine (K). In certain embodiments, X6is D-lysine (Lys). In certain embodiments, X6is a lysine replacement. In certain embodiments, X6is another amino acid.

[0566]

[0117] In certain embodiments, X6is a histidine replacement selected from:

[0567]

[0568] O

[0569]

[0570] o o o o o

[0571] rNx_^ A\AA NC N k N-S' OH

[0572] H2N0or„" A o o -■, o

[0573] A / ? A S A o H2NJYOHH2N\OHH2N\OHH2N\OHH2N\OH / I 0 0 0 6 b

[0574] o

[0575] A A ' A A A H2N^ Y°H 1 H2N]f0HH2N\OHH2N\OHH2N'Y°H

[0576]

[0577] 0 0 o o o Cl

[0578] A - A A

[0579] H2NAf0HHAA H2NA0HHAA1H2NA°H

[0580] 0 0 0 0 0

[0581]

[0582] certain embodiments, X6is a histidine replacement selected from:

[0583]

[0584]

[0118] In certain embodiments, X6is a lysine replacement selected from:

[0585]

[0586]

[0587]

[0119] In certain embodiments, X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent. In certain embodiments, X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent.

[0588]

[0120] In certain embodiments, X7is phenylalanine (F). In certain embodiments, X7is D-phenylalanine (D-Phe). In certain embodiments, X7is a phenylalanine replacement. In certain embodiments, X7is tyrosine (Y). In certain embodiments, X7is D-tyrosine (D-Tyr). In certain embodiments, X7is a tyrosine replacement. In certain embodiments, X7is another amino acid. In certain embodiments, X7is absent.

[0589]

[0121] In certain embodiments, X7is a phenylalanine replacement selected from:

[0590]

[0591]

[0592]

[0593]

[0594]

[0122] In certain embodiments, X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile). In certain embodiments, X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I). In certain embodiments, X8is glycine (G) or sarcosine (Sar).

[0595]

[0123] In certain embodiments, X8is glycine (G). In certain embodiments, X8is a glycine replacement. In certain embodiments, X8is sarcosine (Sar). In certain embodiments, X8is a sarcosine replacement. In certain embodiments, X8is alanine (A). In certain embodiments, X8is D-alanine (D-Ala). In certain embodiments, X8is valine (V). In certain embodiments, X8is D-valine (D-Val). In certain embodiments, X8is leucine (L). In certain embodiments, X8is D-leucine (D-Leu). In certain embodiments, X8is isoleucine (I). In certain embodiments, X8is D-isoleucine (D-Ile).

[0596]

[0124] In certain embodiments, X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile). In certain embodiments, X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I).

[0597]

[0125] In certain embodiments, X9is sarcosine (Sar). In certain embodiments, X9is a sarcosine replacement. In certain embodiments, X9is glycine (G). In certain embodiments, X9is a glycine replacement. In certain embodiments, X9is alanine (A). In certain embodiments, X9is D-alanine (D-Ala). In certain embodiments, X9is valine (V). In certain embodiments, X9is D-valine (D-Val). In certain embodiments, X9is leucine (L). In certain embodiments, X9is D-leucine (D-Leu). In certain embodiments, X9is isoleucine (I). In certain embodiments, X9is D-isoleucine (D-Ile). In certain embodiments, X9is another amino acid.

[0598] OH

[0599]

[0126] In certain embodiments, X9is a sarcosine replacement selected from:

[0600]

[0601]

[0602] OH

[0603] embodiments, X9is a sarcosine replacement selected from:

[0604]

[0605]

[0606]

[0607] OH, and OH. In certain embodiments, X9is a O

[0608] sarcosine replacement selected from:

[0609]

[0610]

[0611] OH incertain embodiments, X9is a

[0612] sarcosine replacement selected from:

[0613]

[0614]

[0615]

[0127] In certain embodiments, X10is JV-methyl-leucine (NMeL), D-JV-methyl-leucine (D-NMeL), N-methyl-aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), D-JV-methyl- glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), '-mcthyl-lysinc (NMeK), D-JV-methyl-lysine (D-NMeK), lysine (K), or D-lysine (D-Lys). In certain embodiments, X10is JV-methyl-leucine (NMeL), D-JV-methyl-leucine (D-NMeL), '-mcthyl-aspartic acid (NMeD), D-JV-methyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), or D- '-mcth l- glutamic acid (D-NMeE). In certain embodiments, X10is '-mcthyl-lcucinc (NMeL), '-mcthyl-aspartic acid (NMeD), N-methyl-glutamic acid (NMeE), glutamic acid (E), '-mcthyl-lysinc (NMeK), or lysine (K). In certain embodiments, X10is JV-methyl -leucine (NMeL), '-mcth l -aspartic acid (NMeD), or '-m eth l -glutamic acid (NMeE). In certain embodiments, X10is A'-mcth l-aspartic acid (NMeD) or A'-mcthy I -glutamic acid (NMeE).

[0616]

[0128] In certain embodiments, X10is A'-mcthyl-lcucinc (NMeL). In certain embodiments, X10is D-JV-methyl -leucine (D-NMeL). In certain embodiments, X10is A'-mcthyl-aspartic acid (NMeD). In certain embodiments, X10is D-A'-mcthyl-aspartic acid (D-NMeD). In certain embodiments, X10is A'-mcthyl-glutamic acid (NMeE). In certain embodiments, X10is D-A'-mcth l-glutamic acid (D-NMeE). In certain embodiments, X10is glutamic acid (E). In certain embodiments, X10is D-glutamic acid (D-Glu). In certain embodiments, X10is A'-mcthyl-lysinc (NMeK). In certain embodiments, X10is D-A'-mcthyl-lysinc (D-NMeK). In certain embodiments, X10is lysine (K). In certain embodiments, X10is D-lysine (D-Lys). In certain embodiments, X10is another amino acid.

[0129] In certain embodiments, X10is a lysine replacement that i

[0617]

[0618] s

[0619]

[0130] In certain embodiments, X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement. In certain embodiments, X11is tyrosine (Y), a tyrosine replacement, phenylalanine (F), or a phenylalanine replacement.

[0620]

[0131] In certain embodiments, X11is tyrosine (Y). In certain embodiments, X11is D-tyrosine (D-Tyr). In certain embodiments, X11is a tyrosine replacement. In certain embodiments, X11is phenylalanine (F). In certain embodiments, X11is D-phenylalanine (D-Phe). In certain embodiments, X11is a phenylalanine replacement.

[0621]

[0132] In certain embodiments, X11is a tyrosine replacement selected from:

[0622]

[0623] . In certain embodiments, X11is a

[0624]

[0625]

[0133] In certain embodiments, X12is proline (P), D-proline (D-Pro), or a proline replacement. In certain embodiments, X12is proline (P) or a proline replacement.

[0626]

[0134] In certain embodiments, X12is proline (P). In certain embodiments, X12is D-proline (D-Pro). In certain embodiments, X12is a proline replacement.

[0627]

[0135] In certain embodiments, X12is a proline replacement selected from:

[0628]

[0629]

[0630]

[0631]

[0136] In certain embodiments, X13is penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), or a cysteine replacement. In certain embodiments, X13is penicillamine (Pen), cysteine (C), or a cysteine replacement.

[0632]

[0137] In certain embodiments, X13is penicillamine (Pen). In certain embodiments, X13is D-penicillamine (D-Pen). In certain embodiments, X13is cysteine (C). In certain embodiments, X13is D-cysteine (D-Cys). In certain embodiments, X13is a cysteine replacement. In certain embodiments, X13is another amino acid.

[0633]

[0138] In certain embodiments, the X3-X13crosslink is a bond, C O alkylene, CMO haloalkylene, C O heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X3-X13crosslink is a bond or CMO heteroalkylene.

[0634]

[0139] In certain embodiments, the X3-X13crosslink is

[0635]

[0636] wherein each a represents the point of attachment to the a-carbon of X3or X13. In certain embodiments,

[0637] the X3-X13crosslink is

[0638]

[0639] ' ', wherein each a represents the point of attachment to the a-

[0640] carbon of X3or X13. In certain embodiments, the X3-X13crosslink is

[0641]

[0642] ' ', wherein each a represents the point of attachment to the a-carbon of X3or X13.

[0643]

[0140] In certain embodiments, X1and X13are crosslinked amino acids connected via an X’-X13crosslink. In certain embodiments, the a-sidechain of X1and the C-terminus of X13are connected to form the X1-X13crosslink. In certain embodiments, the X’-X13crosslink connects the a-carbon of X1and the C-terminus ofX13.

[0644]

[0141] In certain embodiments, the X’-X13crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, CMO alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X’-X13crosslink is CMO heteroalkylene.

[0645]

[0646]

[0142] In certain embodiments, the X'-X13crosslink is O wherein each a represents the point of attachment to the a-carbon of X1or X13.

[0647]

[0143] In certain embodiments, X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

[0648]

[0144] In certain embodiments, X4and X9are crosslinked amino acids connected via an X4-X9crosslink. In certain embodiments, the a-sidechain of X4and the a-amino group of X9are connected to form the X4-X9crosslink. In certain embodiments, the X4-X9crosslink connects the a-carbon of X4and the a-amino group of X9.

[0649]

[0145] In certain embodiments, the X4-X9crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Cg-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X4-X9crosslink is CMO heteroalkylene.

[0650]

[0146] In certain embodiments, the X4-X9crosslink is

[0651]

[0652]

[0653] wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4-X9crosslink is

[0654]

[0655] O, wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4- H N

[0656] X9crosslink is

[0657]

[0658] , wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain

[0659] embodiments, the X4-X9crosslink is

[0660]

[0661] , wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4-X9crosslink is O wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9.

[0662]

[0147] In certain embodiments, X4and X10are crosslinked amino acids connected via an X4-X10crosslink. In certain embodiments, a-sidechains of X4and X10are connected to form the X4-X10crosslink. In certain embodiments, the X4-X10crosslink connects the a-carbons of X4and X10.

[0663]

[0148] In certain embodiments, the X4-X10crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, C O heteroalkenylene, CMO alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Cg-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X4-X10crosslink is CMO heteroalkylene.

[0664]

[0665]

[0149] In certain embodiments, the X4-X10crosslink is O

[0666]

[0667] wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments,

[0668]

[0669] the X4-X10crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments, the X4-X10crosslink is

[0670]

[0671] O, wherein each a represents the point of attachment to the a-carbon of X4

[0672]

[0673] or X10. In certain embodiments, the X4-X10crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments, the X4-X10

[0674] H

[0675]

[0676] a \ p / a

[0677] crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10.

[0678]

[0150] In certain embodiments, X1and X13are crosslinked amino acids connected via an X’-X13crosslink, and X4and X9are crosslinked amino acids connected via an X4-X9crosslink. In certain embodiments, the

[0679]

[0680] X’-X13crosslink is O, wherein each a represents the point of attachment to the a- carbon of X1or X13, and the X4-X9crosslink i

[0681]

[0682] s

[0683]

[0684] wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9.

[0685]

[0151] In certain embodiments, X1and X13are crosslinked amino acids connected via an X’-X13crosslink, and X4and X10are crosslinked amino acids connected via an X4-X10crosslink. In certain embodiments,

[0686]

[0687] the X’-X13crosslink is O, wherein each a represents the point of attachment to the H

[0688] ya

[0689] a-carbon of X1or X13, and the X4-X10crosslink is

[0690]

[0691] O

[0692]

[0693] wherein each a represents the point of attachment to the a-carbon of X4or X10.

[0694] Amino Acid Sequences of REFID NO: 2

[0695]

[0152] In certain embodiments, provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising the amino acid sequence:

[0696] X1-X2-Pen*-X4-G-X6-X7-X8-X9-X10-Y-P-C* (REF ID NO: 2), wherein:

[0697] Pen is penicillamine and * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink;

[0698] X1is arginine (R), D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[0699] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[0700] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), D-glutamic acid (D-Glu), or other amino acid;

[0701] X6is histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid;

[0702] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D- tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;

[0703] X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[0704] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid; and

[0705] X10is A-methyl -leucine (NMeL), D-A-methyl-leucine (D-NMeL), '-mcthy I -aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), D- '-mcthyl- glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), A-methyl-lysine (NMeK), D- '-mcthyl-lysine (D-NMeK), lysine (K), D-lysine (D-Lys), or other amino acid;

[0706] optionally wherein:

[0707] X1and C* are crosslinked amino acids connected via an X’-C* crosslink; and / or

[0708] X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink;

[0709] provided that:

[0710] X1is not R and is not absent; and / or

[0711] X2is not F; and / or

[0712] X9is not Sar; and / or

[0713] X10is not NMeL; and / or

[0714] X1and C* are crosslinked amino acids connected via an X’-C* crosslink; and / or

[0715] X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

[0716]

[0153] In certain embodiments, X1is not R and is not absent.

[0717]

[0154] In certain embodiments, X2is not F.

[0718]

[0155] In certain embodiments, X9is not Sar.

[0719]

[0156] In certain embodiments, X10is not NMeL.

[0720]

[0157] In certain embodiments, X1and C* are crosslinked amino acids connected via an X’-C* crosslink.

[0721]

[0158] In certain embodiments, X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

[0722]

[0159] In certain embodiments of REF ID NO: 2,

[0723] X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[0724] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;

[0725] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid; X6is histidine (H), D-histidine (D-His), a histidine replacement, or other amino acid;

[0726] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;

[0727] X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[0728] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid; and

[0729] X10is A-methyl -leucine (NMeL), D-A-methyl-leucine (D-NMeL), '-mcthy I -aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), D- '-mcthyl- glutamic acid (D-NMeE), or other amino acid.

[0730]

[0160] In certain embodiments of REF ID NO: 2,

[0731] X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent;

[0732] X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;

[0733] X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;

[0734] X6is histidine (H), D-histidine (D-His), or a histidine replacement;

[0735] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;

[0736] X8is glycine (G) or sarcosine (Sar);

[0737] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile); and

[0738] X10is A-methyl -leucine (NMeL), D-A-methyl-leucine (D-NMeL), A-methyl -aspartic acid (NMeD), D-A-methyl-aspartic acid (D-NMeD), A-methyl-glutamic acid (NMeE), or D-A-methyl-glutamic acid (D-NMeE).

[0739]

[0161] In certain embodiments of REF ID NO: 2,

[0740] X1is arginine (R), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent;

[0741] X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;

[0742] X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement;

[0743] X6is histidine (H) or a histidine replacement; X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;

[0744] X8is glycine (G) or sarcosine (Sar);

[0745] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I); and

[0746] X10is A'-mcthyl-lcucinc (NMeL), '-mcthyl-aspartic acid (NMeD), or JV-methyl-glutamic acid (NMeE).

[0747]

[0162] In certain embodiments, X1is arginine (R), D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), aspartic acid (D), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent. In certain embodiments, X1is arginine (R), asparagine (N), or leucine (L), or is absent.

[0748]

[0163] In certain embodiments, X1is arginine (R). In certain embodiments, X1is D-arginine (D-Arg). In certain embodiments, X1is aspartic acid (D). In certain embodiments, X1is D-aspartic acid (D-Asp). In certain embodiments, X1is asparagine (N). In certain embodiments, X1is D-asparagine (D-Asn). In certain embodiments, X1is glutamine (Q). In certain embodiments, X1is D-glutamine (D-Gln). In certain embodiments, X1is leucine (L). In certain embodiments, X1is D-leucine (D-Leu). In certain embodiments, X1is lysine (K). In certain embodiments, X1is D-lysine (Lys). In certain embodiments, X1is a lysine replacement. In certain embodiments, X1is another amino acid. In certain embodiments, X1is absent.

[0749] f l

[0750] H2N^y0H

[0751]

[0164] In certain embodiments, X1is a lysine replacement selected from:

[0752]

[0753] O

[0754]

[0755] X1is a lysine replacement that i

[0756]

[0757] s O

[0758] O

[0759]

[0165] In certain embodiments, X4is another amino acid that is

[0760]

[0761] O

[0762]

[0166] In certain embodiments, X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), a tyrosine replacement, histidine (H), a histidine replacement, lysine (K), or a lysine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent. In certain embodiments, X2is phenylalanine (F), or is absent.

[0763]

[0167] In certain embodiments, X2is phenylalanine (F). In certain embodiments, X2is D-phenylalanine (D-Phe). In certain embodiments, X2is a phenylalanine replacement. In certain embodiments, X2is tyrosine (Y). In certain embodiments, X2is D-tyrosine (D-Tyr). In certain embodiments, X2is a tyrosine replacement. In certain embodiments, X2is histidine (H). In certain embodiments, X2is D-histidine (D-His). In certain embodiments, X2is a histidine replacement. In certain embodiments, X2is lysine (K). In certain embodiments, X2is D-lysine (Lys). In certain embodiments, X2is a lysine replacement. In certain embodiments, X2is another amino acid. In certain embodiments, X2is absent.

[0764]

[0168] In certain embodiments, X2is a phenylalanine replacement selected from:

[0765]

[0766]

[0767] phenylalanine replacement that i

[0768]

[0769] s. In certain embodiments, X2is a tyrosine replacement that is

[0770] H2N

[0771]

[0772] selected from:

[0773]

[0774]

[0169] In certain embodiments, X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D -serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), or D-glutamic acid (D-Glu). In certain embodiments, X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), a lysine replacement, aspartic acid (D), or glutamic acid (E). In certain embodiments, X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement. In certain embodiments, X4is threonine (T) or lysine (K).

[0775]

[0170] In certain embodiments, X4is threonine (T). In certain embodiments, X4is D-threonine (D-Thr). In certain embodiments, X4is a threonine replacement. In certain embodiments, X4is serine (S). In certain embodiments, X4is D-serine (D-Ser). In certain embodiments, X4is a serine replacement. In certain embodiments, X4is lysine (K). In certain embodiments, X4is D-lysine (Lys). In certain embodiments, X4is a lysine replacement. In certain embodiments, X4is aspartic acid (D). In certain embodiments, X4is D-aspartic acid (D-Asp). In certain embodiments, X4is glutamic acid (E). In certain embodiments, X4is D-glutamic acid (D-Glu). In certain embodiments, X4is another amino acid.

[0776] NH2H2N

[0171] In certain embodiments, X4is a lysine replacement selected from:

[0777]

[0778]

[0779]

[0780] In certain embodiments, X4is another

[0781] amino acid that is O. In certain embodiments, X4is a lysine replacement that is

[0782] NH2

[0783] OH

[0784] H2N

[0785]

[0786] O

[0787]

[0172] In certain embodiments, X6is histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, X6is histidine (H), D-histidine (D-His), or a histidine replacement. In certain embodiments, X6is histidine (H), a histidine replacement, lysine (K), or a lysine replacement. In certain embodiments, X6is histidine (H) or a histidine replacement.

[0788]

[0173] In certain embodiments, X6is histidine (H). In certain embodiments, X6is D-histidine (D-His). In certain embodiments, X6is a histidine replacement. In certain embodiments, X6is lysine (K). In certain embodiments, X6is D-lysine (Lys). In certain embodiments, X6is a lysine replacement. In certain embodiments, X6is another amino acid.

[0789]

[0174] In certain embodiments, X6is a histidine replacement selected from:

[0790]

[0791] O 0 0 0 0 0

[0792] N^TI N-NHHA A

[0793] □ A / H H IAOHH N\-OHH NA kOHH? kVOHi o ri2^ [f M2N TT H2N IT H2N T| H2N |T I / ' o o o b b

[0794]

[0795] A A ’ A X - X H M2JN V IT0H 1H H2INA IT<0HH H2NNA [j<0HH M2INA i<f0HH H2NNA T<f0Ho o 0 0 0

[0796] Cl X s X % 'X) X?cX i H H2INA |T<0HH H2AN T< TOHH H2NNA [T<0HH H2NNA T<]OHH H2INA IT<0H0 0 o o o

[0797]

[0798] In certain embodiments, X6is a histidine replacement selected from

[0799]

[0800] o o NH

[0801] 0 0 0 0 O

[0802]

[0803] 0 0 o 0 0

[0804]

[0805] certain embodiments, X6is a histidine replacement selected from

[0806]

[0807]

[0175] In certain embodiments, X6is a lysine replacement selected from:

[0808]

[0809] and

[0810]

[0811]

[0176] In certain embodiments, X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent. In certain embodiments, X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent.

[0812]

[0177] In certain embodiments, X7is phenylalanine (F). In certain embodiments, X7is D-phenylalanine (D-Phe). In certain embodiments, X7is a phenylalanine replacement. In certain embodiments, X7is tyrosine (Y). In certain embodiments, X7is D-tyrosine (D-Tyr). In certain embodiments, X7is a tyrosine replacement. In certain embodiments, X7is another amino acid. In certain embodiments, X7is absent.

[0813] MeO

[0814] H2NOH

[0178] In certain embodiments, X7is a phenylalanine replacement selected from:

[0815]

[0816] O

[0817]

[0818]

[0819]

[0179] In certain embodiments, X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile). In certain embodiments, X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I). In certain embodiments, X8is glycine (G) or sarcosine (Sar).

[0820]

[0180] In certain embodiments, X8is glycine (G). In certain embodiments, X8is a glycine replacement. In certain embodiments, X8is sarcosine (Sar). In certain embodiments, X8is a sarcosine replacement. In certain embodiments, X8is alanine (A). In certain embodiments, X8is D-alanine (D-Ala). In certain embodiments, X8is valine (V). In certain embodiments, X8is D-valine (D-Val). In certain embodiments, X8is leucine (L). In certain embodiments, X8is D-leucine (D-Leu). In certain embodiments, X8is isoleucine (I). In certain embodiments, X8is D-isoleucine (D-Ile).

[0821]

[0181] In certain embodiments, X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile). In certain embodiments, X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I).

[0822]

[0182] In certain embodiments, X9is sarcosine (Sar). In certain embodiments, X9is a sarcosine replacement. In certain embodiments, X9is glycine (G). In certain embodiments, X9is a glycine replacement. In certain embodiments, X9is alanine (A). In certain embodiments, X9is D-alanine (D-Ala). In certain embodiments, X9is valine (V). In certain embodiments, X9is D-valine (D-Val). In certain embodiments, X9is leucine (L). In certain embodiments, X9is D-leucine (D-Leu). In certain embodiments, X9is isoleucine (I). In certain embodiments, X9is D-isoleucine (D-Ile). In certain embodiments, X9is another amino acid.

[0823] OH

[0824]

[0183] In certain embodiments, X9is a sarcosine replacement selected from:

[0825]

[0826] OH

[0827]

[0828] embodiments, X9is a sarcosine replacement selected from:

[0829]

[0830] OH OH OH OH OH OH

[0831]

[0832] sarcosine replacement selected from:

[0833]

[0834]

[0835] sarcosine replacement selected from:

[0836]

[0837]

[0838]

[0184] In certain embodiments, X10is JV-methyl-leucine (NMeL), D-JV-methyl-leucine (D-NMeL), N-methyl-aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), D-JV-methyl- glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), '-mcthyl-lysinc (NMeK), D-JV-methyl-lysine (D-NMeK), lysine (K), or D-lysine (D-Lys). In certain embodiments, X10is JV-methyl-leucine (NMeL), D-JV-methyl-leucine (D-NMeL), '-mcthyl-aspartic acid (NMeD), D-JV-methyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), or D- '-mcth l- glutamic acid (D-NMeE). In certain embodiments, X10is '-mcthyl-lcucinc (NMeL), A'-mcthyl-aspartic acid (NMeD), N-methyl-glutamic acid (NMeE), glutamic acid (E), '-mcthyl-lysinc (NMeK), or lysine (K). In certain embodiments, X10is JV-methyl -leucine (NMeL), '-mcth l -aspartic acid (NMeD), or '-m eth l -glutamic acid (NMeE). In certain embodiments, X10is A'-mcth l-aspartic acid (NMeD) or A'-mcthy I -glutamic acid (NMeE).

[0185] In certain embodiments, X10is JV-methyl-leucine (NMeL). In certain embodiments, X10is D-JV-methyl -leucine (D-NMeL). In certain embodiments, X10is '-mcthy I -aspartic acid (NMeD). In certain embodiments, X10is D- '-mcthyl-aspartic acid (D-NMeD). In certain embodiments, X10is '-mcthyl-glutamic acid (NMeE). In certain embodiments, X10is D- '-mcthyl-gliitamic acid (D-NMeE). In certain embodiments, X10is glutamic acid (E). In certain embodiments, X10is D-glutamic acid (D-Glu). In certain embodiments, X10is JV-methyl-lysine (NMeK). In certain embodiments, X10is D-JV-methyl-lysine (D-NMeK). In certain embodiments, X10is lysine (K). In certain embodiments, X10is D-lysine (D-Lys). In certain embodiments, X10is another amino acid.

[0839]

[0186] In certain embodiments, X10is a lysine replacement that

[0840]

[0841] is

[0842]

[0187] In certain embodiments, a-sidechains of Pen* and C* are connected to form the Pen*-C* crosslink. In certain embodiments, the Pen*-C* crosslink connects the a-carbons of Pen* and C*.

[0843]

[0188] In certain embodiments, the Pen*-C* crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, CMO alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the Pen*-C* crosslink is a bond or CMO heteroalkylene.

[0844] aAxS-Sx^\a

[0845]

[0189] In certain embodiments, the Pen*-C* crosslink is / ' or

[0846]

[0847] / ', wherein each a represents the point of attachment to the a-carbon of Pen* oraZ / S-sA0

[0848] C*. In certain embodiments, the Pen*-C* crosslink is ' ', wherein each a represents the point of attachment to the a-carbon of Pen* or C*. In certain embodiments, the Pen*-C* crosslink is

[0849] , wherein each a represents the point of attachment to the a-carbon of Pen* or

[0850]

[0851]

[0190] In certain embodiments, X1and C* are crosslinked amino acids connected via an X’-C* crosslink. In certain embodiments, the a-sidechain of X1and the C-terminus of C* are connected to form the X’-C* crosslink. In certain embodiments, the X’-C* crosslink connects the a-carbon of X1and the C-terminus ofC*.

[0852]

[0191] In certain embodiments, the X’-C* crosslink is a bond, C O alkylene, C O haloalkylene, C O heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X’-C* crosslink is Ci-w heteroalkylene.

[0853]

[0854]

[0192] In certain embodiments, the X'-C* crosslink is O wherein each a represents the point of attachment to the a-carbon of X1or C*.

[0855]

[0193] In certain embodiments, X4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

[0856]

[0194] In certain embodiments, X4and X9are crosslinked amino acids connected via an X4-X9crosslink. In certain embodiments, the a-sidechain of X4and the a-amino group of X9are connected to form the X4-X9crosslink. In certain embodiments, the X4-X9crosslink connects the a-carbon of X4and the a-amino group of X9.

[0857]

[0195] In certain embodiments, the X4-X9crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X4-X9crosslink is CMO heteroalkylene.

[0858]

[0859]

[0196] In certain embodiments, the X4-X9crosslink is O

[0860]

[0861] wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4-X9crosslink is

[0862]

[0863] O, wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4- H N

[0864] X9crosslink is

[0865]

[0866] , wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain

[0867]

[0868] embodiments, the X4-X9crosslink is O, wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4-X9crosslink is O wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9.

[0869]

[0197] In certain embodiments, X4and X10are crosslinked amino acids connected via an X4-X10crosslink. In certain embodiments, a-sidechains of X4and X10are connected to form the X4-X10crosslink. In certain embodiments, the X4-X10crosslink connects the a-carbons of X4and X10.

[0870]

[0198] In certain embodiments, the X4-X10crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, C O heteroalkenylene, CMO alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Cg-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X4-X10crosslink is CMO heteroalkylene.

[0871]

[0872]

[0199] In certain embodiments, the X4-X10crosslink is O

[0873]

[0874] wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments,

[0875]

[0876] the X4-X10crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments, the X4-X10crosslink is

[0877]

[0878] O, wherein each a represents the point of attachment to the a-carbon of X4

[0879]

[0880] or X10. In certain embodiments, the X4-X10crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments, the X4-X10

[0881] H

[0882]

[0883] a \ fl / a

[0884] crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10.

[0885]

[0200] In certain embodiments, X1and C* are crosslinked amino acids connected via an X’-C* crosslink, and X4and X9are crosslinked amino acids connected via an X4-X9crosslink. In certain embodiments, the

[0886]

[0887] X’-C* crosslink is O, wherein each a represents the point of attachment to the a- carbon of X1or C*, and the X4-X9crosslink i

[0888]

[0889] s

[0890]

[0891] wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9.

[0892]

[0201] In certain embodiments, X1and C* are crosslinked amino acids connected via an X’-C* crosslink, and X4and X10are crosslinked amino acids connected via an X4-X10crosslink. In certain embodiments,

[0893]

[0894] the X’-C* crosslink is O, wherein each a represents the point of attachment to the

[0895] a-carbon of X1or C*, and the X4-X10crosslink is

[0896]

[0897] O

[0898]

[0899] wherein each a represents the point of attachment to the a-carbon of X4or X10.

[0900] Modified Amino Acid Sequences of REFID NO: A

[0901]

[0202] In certain embodiments, provided herein are cyclic peptides, and pharmaceutically acceptable salts thereof, comprising the amino acid sequence:

[0902] R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* (REF ID NO: A), wherein:

[0903] Pen is penicillamine, Sar is sarcosine, and NMeL is '-mcthyl-lcucinc. and * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink; and

[0904] the amino acid sequence comprises at least one amino acid substitution or deletion (e.g., 1, 2, or 3 amino acid substitutions or deletions) at amino acid positions Rl, F2, T4, H6, F7, G8, Sar9, and / or NMeLlO of REF ID NO: A.

[0905]

[0203] In certain embodiments, the amino acid sequence comprises one or two amino acid substitutions at positions Rl, F2, T4, H6, F7, G8, Sar9, and / or NMeLlO. In certain embodiments, the amino acid sequence comprises one amino acid substitution at position Rl, F2, T4, H6, F7, G8, Sar9, or NMeLlO. In certain embodiments, the amino acid sequence comprises one or two amino acid deletions at positions Rl, F2, T4, H6, F7, G8, Sar9, and / or NMeLlO. In certain embodiments, the amino acid sequence comprises one amino acid deletion at positions Rl, F2, T4, H6, F7, G8, Sar9, or NMeLlO.

[0906]

[0204] In certain embodiments, Rl is substituted with D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, R1 is substituted with D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, R1 is substituted with asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent. In certain embodiments, R1 is substituted with asparagine (N), or leucine (L), or is absent.

[0907]

[0205] In certain embodiments, R1 is substituted with lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, R1 is substituted with a lysine replacement. In certain embodiments, R1 is

[0908] substituted with a lysine replacement selected from:

[0909]

[0910] O, O

[0911]

[0912] u, and u UH

[0913] In certain embodiments, R1 is substituted with a lysine replacement that i

[0914]

[0915] s O

[0206] In certain embodiments, R1 is replaced by X1.

[0916]

[0207] In certain embodiments, F2 is substituted with D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement, or is absent. In certain embodiments, F2 is substituted with D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent. In certain embodiments, F2 is substituted with a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent. In certain embodiments, F2 is absent.

[0917]

[0208] In certain embodiments, F2 is substituted with D-phenylalanine (D-Phe) or a phenylalanine replacement. In certain embodiments, F2 is substituted with a phenylalanine replacement. In certain ^X / SO3H

[0918] H2N'Y, Hembodiments, F2 is substituted with a phenylalanine replacement selected from:

[0919]

[0920] O

[0921]

[0922] substituted with a phenylalanine replacement that i

[0923]

[0924] s O

[0925]

[0209] In certain embodiments, E2 is replaced by X2.

[0926]

[0210] In certain embodiments, T4 is substituted with D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), or D-glutamic acid (D-Glu). In certain embodiments, T4 is substituted with D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, T4 is substituted with a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement. In certain embodiments, T4 is substituted with lysine (K).

[0927]

[0211] In certain embodiments, T4 is substituted with lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, T4 is substituted with a lysine replacement. In certain embodiments, T4 is substituted with lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, T4 is

[0928]

[0929]

[0930] substituted with a lysine replacement that

[0931]

[0932] is In certain embodiments, T4 is

[0933] substituted with another amino acid that i

[0934]

[0935] s O In certain embodiments, T4 is substituted with O

[0936] H2N\0H

[0937] another amino acid that is

[0938]

[0939] O

[0940]

[0212] In certain embodiments, T4 is replaced by X4.

[0941]

[0213] In certain embodiments, H6 is substituted with D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement. In certain embodiments, H6 is substituted with D-histidine (D-His), or a histidine replacement. In certain embodiments, H6 is substituted with a histidine

[0942]

[0943] O A A ' X1X - X H ri2A^ Tf"OH 1H H2INA T<fOHH H2NNA T<fOHH rl2N^A T<fOHH H2 / N V TfOHo o 0 0 0

[0944] Cl A A X X X H M2NNV Tf H H2NNA TTf0HH H2NN^^ IT0HH H2NNA T< TOHH H2NNA IT<0H0 0 o o o

[0945]

[0946]

[0947] certain embodiments, the histidine replacement selected from

[0948]

[0949]

[0214] In certain embodiments, H6 is substituted with a lysine replacement. In certain embodiments, the lysine replacement selected from

[0950]

[0951] :

[0952]

[0215] In certain embodiments, H6 is replaced by X6.

[0953]

[0216] In certain embodiments, F7 is substituted with D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent. In certain embodiments, F7 is substituted with a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent. In certain embodiments, F7 is substituted with a phenylalanine replacement

[0954] selected from

[0955]

[0956] F H #F / O r6h / / 1H / Y* H2NJY0HH2NJY°HH. N-'Y^ / ' o O 0 0 0

[0957] / F Xl,, " X l " X iHH21NA TYTOHH H2 / IN V ITOHH H2INA IT<OHH H2INA IT<0H0 0 0 0

[0958]

[0959]

[0960] O, and O. In certain embodiments, F7 is substituted with a

[0961] phenylalanine replacement that i

[0962]

[0963] s O

[0964]

[0217] In certain embodiments, F7 is replaced by X7.

[0965]

[0218] In certain embodiments, G8 is substituted with a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile). In certain embodiments, G8 is substituted with a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I). In certain embodiments, G8 is substituted with sarcosine (Sar).

[0966]

[0219] In certain embodiments, G8 is replaced by X8.

[0967]

[0220] In certain embodiments, Sar9 is substituted with a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile). In certain embodiments, Sar9 is substituted with a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I). In

[0968]

[0969]

[0970] OH

[0971] embodiments, Sar9 is substituted with a sarcosine replacement selected from:

[0972]

[0973] OH OH OH OH OH OH OH

[0974]

[0975] O

[0976] embodiments, Sar9 is substituted with a sarcosine replacement selected from:

[0977]

[0978]

[0979] embodiments, Sar9 is substituted with a sarcosine replacement selected from:

[0980]

[0981]

[0982]

[0221] In certain embodiments, Sar9 is replaced by X9.

[0983]

[0222] In certain embodiments, NMeLlO is substituted with D- '-mcthyl-lcucinc (D-NMeL), '-mcthyl-aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), D-JV-methyl- glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), JV-methyl-lysine (NMeK), D-JV-methyl-lysine (D-NMeK), lysine (K), or D-lysine (D-Lys). In certain embodiments, NMeLlO is substituted with D-JV-methyl-leucine (D-NMeL), '-mcthyl-aspartic acid (NMeD), D- '-mcthyl-aspartic acid (D-NMeD), '-mcthyl-glutamic acid (NMeE), or D- '-mcthyl- glutamic acid (D-NMeE). In certain embodiments, NMeLlO is substituted with '-mcthy I -aspartic acid (NMeD), or '-mcthy I -glutamic acid (NMeE). In certain embodiments, NMeLlO is substituted with '-mcthyl -glutamic acid (NMeE).

[0984]

[0223] In certain embodiments, NMeLlO is substituted with a lysine replacement that is

[0985] NH2

[0986]

[0987] 0

[0988]

[0224] In certain embodiments, NMeLlO is replaced by X10.

[0989]

[0225] In certain embodiments, a-sidechains of Pen* and C* are connected to form the Pen*-C* crosslink. In certain embodiments, the Pen*-C* crosslink connects the a-carbons of Pen* and C*.

[0990]

[0226] In certain embodiments, the Pen*-C* crosslink is a bond, CMO alkylene, C O haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, CMO alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Cg-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the Pen*-C* crosslink is a bond or CMO heteroalkylene.

[0991]

[0227] In certain embodiments, the Pen*-C* crosslink is

[0992]

[0993] / \ or

[0994]

[0995] / \, wherein each a represents the point of attachment to the a-carbon of Pen* or

[0996] C*. In certain embodiments, the Pen*-C* crosslink is

[0997]

[0998] ' ', wherein each a represents the point of attachment to the a-carbon of Pen* or C*. In certain embodiments, the Pen*-C* crosslink is a J? c a X a

[0999]

[1000] / \, wherein each a represents the point of attachment to the a-carbon of Pen* or C*.

[1001]

[0228] In certain embodiments, R1 is replaced withX1, and X1and C* are crosslinked amino acids connected via an X’-C* crosslink. In certain embodiments, the a-sidechain of X1and the C-terminus of C* are connected to form the X'-C* crosslink. In certain embodiments, the X'-C* crosslink connects the a-carbon of X1and the C-terminus of C*.

[1002]

[0229] In certain embodiments, the X’-C* crosslink is a bond, CMO alkylene, C O haloalkylene, CMO heteroalkylene, C O alkenylene, C O heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Cg-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X’-C* crosslink is CMO heteroalkylene. H

[1003] N

[1004] a

[1005]

[0230] In certain embodiments, the X’-C* crosslink is O, wherein each a represents the point of attachment to the a-carbon of X1or C*.

[1006]

[0231] In certain embodiments, T4 and Sar9 are replaced by X4and X9, respectively, and X4and X9are crosslinked amino acids connected via an X4-X9crosslink; or T4 and NMeLlO are replaced by X4and X10, respectively, and X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

[1007]

[0232] In certain embodiments, the a-sidechain of X4and the a-amino group of X9are connected to form the X4-X9crosslink. In certain embodiments, the X4-X9crosslink connects the a-carbon of X4and the a- amino group of X9.

[1008]

[0233] In certain embodiments, the X4-X9crosslink is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X4-X9crosslink is CMO heteroalkylene.

[1009] H

[1010] a

[1011]

[1012]

[0234] In certain embodiments, the X4-X9crosslink is O

[1013] H H

[1014] N a N

[1015]

[1016] O, or O wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4-X9crosslink is

[1017] H

[1018] N

[1019]

[1020] o, wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain embodiments, the X4- H

[1021] N

[1022]

[1023] X9crosslink is O, wherein the a represents the point of attachment to the a- carbon of X4, and the • represents the point of attachment to the a-amino group of X9. In certain

[1024] N

[1025] embodiments, the X4-X9crosslink is

[1026]

[1027] , wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of a H

[1028] N

[1029]

[1030] X9. In certain embodiments, the X4-X9crosslink is O, wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9.

[1031]

[0235] In certain embodiments, a-sidechains of X4and X10are connected to form the X4-X10crosslink. In certain embodiments, the X4-X10crosslink connects the a-carbons of X4and X10.

[1032]

[0236] In certain embodiments, the X4-X10crosslink is a bond, Cnio alkylene, Cnio haloalkylene, Cnio heteroalkylene, Cnio alkenylene, Cnio heteroalkenylene, Cnio alkynylene, Cnio heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, the X4-X10crosslink is Cnio heteroalkylene.

[1033] H

[1034]

[1035] a\ n / a

[1036]

[0237] In certain embodiments, the X4-X10crosslink is O,

[1037]

[1038] wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments,

[1039] H

[1040] . N.

[1041]

[1042] a\ r / a

[1043] the X4-X10crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments, the X4-X10crosslink is

[1044]

[1045] O, wherein each a represents the point of attachment to the a-carbon of X4

[1046]

[1047] or X10. In certain embodiments, the X4-X10crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10. In certain embodiments, the X4-X10

[1048] H

[1049]

[1050] a\ |] / a

[1051] crosslink is O, wherein each a represents the point of attachment to the a-carbon of X4or X10.

[1052]

[1053]

[0238] In certain embodiments, the X'-C* crosslink is O wherein each a represents the point of attachment to the a-carbon of X1or C*, and the X4-X9crosslink is

[1054]

[1055] O, wherein the a represents the point of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of X9.

[1056]

[1057]

[0239] In certain embodiments, the X'-C* crosslink is O wherein each a represents the point of attachment to the a-carbon of X1or C*, and the X4-X10crosslink is

[1058] H

[1059]

[1060] a \ [] / aO, wherein each a represents the point of attachment to the a-carbon of X4orX10.

[1061] Additional Embodiments of Amino Acid Sequences of REF ID NOs: 1, 2, and A

[1062]

[0240] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises one of the following amino acid sequences:

[1063] REF REF ID Sequence ID Sequence

[1064] NO: NO:

[1065] 3 F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 4 I< -F-Pcn*-T-G-H-F-G-Sar-NMcL-Y-P-C* 5 R-F-Pen*-Kt-G-H-F-G-X9At-NMeL-Y-P-C* 6 R-F-Pen*-Kt-G-H-F-G-Sar-NMeDt-Y-P-C* 7 R-F-Pcn*-K -G-H-F-G-Sar-NMcE -Y-P-C* 8 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 9 N-F-Pen*-T-G-H-F-G-X9B-NMeL-Y-P-C* 10 N-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 11 N-F-Pen*-T-G-H-X7A-G-Sar-NMeL-Y-P-C* 12 L-F-Pen*-T-G-H-X7A-G-Sar-NMeL-Y-P-C* 13 L-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 14 N-F-Pen*-T-G-H-F-G-X9C-NMeL-Y-P-C* 15 L-F-Pen*-T-G-H-F-G-X9C-NMeL-Y-P-C* 16 Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 17 N-F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 18 F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 19 R-F-Pen*-Kt-G-H-F-G-X9C-NMeEt-Y-P-C* 20 Kl-F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C*t 21 N-F-Pen*-Kt-G-H-X7A-G-Sar-NMeEt-Y-P-C* 22 N-F-Pen*-T-G-X6A-F-G-Sar-NMeL-Y-P-C* 23 N-F-Pen*-T-G-X6A-F-G-X9C-NMeL-Y-P-C* 24 N-F-Pen*-T-G-X6B-F-G-Sar-NMeL-Y-P-C* 25 F-Pen*-T-G-X6A-F-G-Sar-NMeL-Y-P-C* 26 F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-P-C* 98 X1A-F-Pen*-X4At-G-X6C-F-G-IDA-NMeEt-Y-P-C* 99 N-F-Pen*-X4At-G-X6C-F-G-IDA-NMeEt-Y-P-C* 100 X1A-F-Pen*-Et-G-X6C-F-G-IDA-NMeKt-Y-P-C* 101 N-F-Pen*-X4At-G-X6C-F-G-Sar-NMeEt-Y-P-C* 102 N-F-Pen*-X4At-G-X6D-F-G-Sar-NMeEt-Y-P-C* 103 X1A-X2A-Pen*-X4At-G-X®-F-G-Sar-NMeEt-Y-P- C*

[1066] 104 N-F-Pcn*-Xl' -G-X'l,-F-G-IDA-NMcE -Y-P-C* 105 Xl'-F-Pcn*-Xl' -G-X6l,-F-G-Sar-NMcE -Y-P-C* 106 Xl'-F-Pcn*-Xl' -G-X9l,-F-G-IDA-NMcE -Y-P- 107 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P-C*

[1067] C*

[1068] 220 D-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 221 R-F-Pcn*-E -G-EI-F-G-Sar-NMcI< -Y-P-C* 222 R-F-Pen*-K-G-H-F-G-Sar-NMeL-Y-P-C* 223 X1A-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 224 Q-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 225 Q-F-Pen*-T-G-H-X7A-G-Sar-NMeL-X11A-P-C* 226 N-F-Pen*-T-G-H-X7B-G-Sar-NMeL-Y-P-C* 227 (D-Leu)-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 228 (D-Asn)-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 229 R-F-Pen*-T-G-X6E-F-G-Sar-NMeL-Y-P-C* 230 R-F-Pe^-T-G-X^-F-G-Sar-NMeL-Y-P-C* 231 Xl'-F-Pcn*-Xl' -G-X6 i-F-G-IDA-NMcE -Y-P-C* 232 R-F-Pen*-T-G-X®-X7C-G-Sar-NMeL-Y-P-C* 233 R-F-Pen*-T-G-X®-X7D-G-Sar-NMeL-Y-P-C* 234 Xl'-F-Pcn*-Xl' -G-X9ll-F-G-IDA-NMcE -Y-P-C* 235 X1A-F-Pen*-X4At-G-X6I-F-G-IDA-NMeEt-Y-P-C* 236 X1A-F-Pen*-X4At-G-X®-F-G-X9D-NMeEt-Y-P-C* 237 Xl''-F-Pcn*-Xl'' -G-X6' -XA-G-IDA-NMcE -Y-P- C*

[1069] 238 X1A-F-Pen*-X4At-G-X6C-F-G-X9D-NMeEt-Y-P-C* 239 X1A-F-Pen*-X4At-G-X6D-F-G-X9E-NMeEt-Y-P-C* 240 X1A-F-Pen*-X4At-G-X6D-F-G-X9F-NMeEt-Y-P-C* 241 X1A-F-Pen*-X4At-G-X6C-F-G-X9F-NMeEt-Y-P-C* 242 X1A-F-Pen*-X4At-G-X6C-F-G-X9E-NMeEt-Y-P-C* 243 X1A-F-Pen*-X4At-G-X®-F-G-X9G-NMeEt-Y-P-C* 244 X1A-F-Pen*-X4At-G-X®-F-G-X9H-NMeEt-Y-P-C* 245 R-F-Pen*-T-G-X6I-F-G-Sar-NMeL-Y-P-C*

[1070]

[1071] 246 R-F-Pen*-T-G-X6K-F-G-Sar-NMeL-Y-P-C* 247 R-F-Pen*-T-G-X6C-X7F-G-Sar-NMeL-Y-P-C* REF REF

[1072] ID Sequence ID Sequence

[1073] NO: NO:

[1074] 248 Xl'-F-Pcn*-E -G-X9l-Xi-G-IDA-NMcI< -Y-P-C* 249 Xl''-F-Pcn*-Xl'' -G-X9l-X, i-G-IDA-NMcE -Y-P- C*

[1075] 250 Xl'-F-Pcn*-Xl' -G-X6l-F-G-IDA-NMcE -Y-P-C* 251 Xl'-F-Pcn*-Xl' -G-X9l-F-G-IDA-NMcE -Y-P-C* 252 X1A-F-Pen*-X4A^-G-X®-F-G-IDA-NMeE^-Y-P-C* 253 Xl'-F-Pcn*-Xl' -G-X6 l-F-G-IDA-NMcE -Y-P- C*

[1076] 254 Xl'-F-Pcn*-Xl' -G-X9-F-G-IDA-NMcE -Y-P-C* 255 E-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 256 R-F-Pen*-N-G-H-F-G-Sar-NMeL-Y-P-C* 257 (D-Asn)-F-Pen*-T-G-H-X7B-G-Sar-NMeL-Y-P-C* 258 XI A-F-Pcn*-K -G-H-F-G-Sar-NMcE -Y-P-C* 259 Xl'-F-Pcn*-E -G-X69-F-G-IDA-NMcI< -Y-X12'- C*

[1077] 260 Xl'-F-Pcn*-Xl' -G-X69-F-G-IDA-NMcE -Y- 261 Xl'-F-Pcn*-E -G-X6' -F-G-X9l-NMcI< -Y-P-C*

[1078] X12A-C*

[1079] 262 Xl'-F-Pcn*-E -G-X9' -F-G-X9l-NMcI< -Y-P-C* 263 Xl'-F-Pcn*-Xl' -G-X6' -F-G-X9l-NMcE -Y-P-C* 264 Xl'-F-Pcn*-Xl' -G-X9' -F-G-X9l-NMcE -Y-P-C* 265 Xl'-F-Pcn*-Xl' -G-X9l,-F-G-X9'-NMcE -Y-P-C* 266 Xl'-F-Pcn*-Xl' -G-X9l,-F-G-X9K-NMcE -Y-P-C* 267 Xl'-F-Pcn*-Xll' -G-X6' -F-G-IDA-NMcI< -Y-P-C* 268 Xl''-F-Pcn*-Xl'' -G-X69-XG I-G-IDA-NMcE -Y-P- 269 Xl'-F-Pcn*-Xl' -G-X6,-F-G-IDA-NMcE -Y-P-C*

[1080] C*

[1081] 270 Xl'-F-Pcn*-E -G-X9l-F-G-IDA-NMcI< -Y-P-C* 271 Xl'-F-Pcn*-E -G-X9 l-F-G-IDA-NMcI< -Y-P-C* 272 Xl'-F-Pcn*-E -G-X9l-F-G-IDA-NMcI< -Y-P-C* 273 Xl'-F-Pcn*-E -G-X6l-F-G-IDA-NMcI< -Y-P-C* 274 X1A-F-Pen*-X4At-G-X6C-F-G-X9L-NMeEt-Y-P-C* 284 X1A-F-Pen*-X4B-G-X6D-F-G-Sar-NMeL-Y-P-C* 285 R-F-Pen*-T-G-H-X7I-G-Sar-NMeL-Y-P-C* 286 R-F-Pen*-T-G-X6P-F-G-Sar-NMeL-Y-P-C* 287 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12B-C* 288 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12C-C* 289 R-F-Pen*-T-G-X6Q-F-G-Sar-NMeL-Y-P-C* 290 I< -F-Pcn*-Xl9-G-H-F-G-Sar-NMcL-Y-P-C* 291 K -F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 292 R-F-Pen*-T-G-X6R-F-G-Sar-NMeL-Y-P-C* 293 R-F-Pen*-T-G-H-X7I-G-Sar-NMeL-Y-P-C* 294 R-F-Pen*-T-G-H-F-G-Sar-NMeL-X11B-P-C* 295 R-F-Pen*-T-G-H-X7K-G-Sar-NMeL-Y-P-C* 296 R-F-Pen*-T-G-H-X7M-G-Sar-NMeL-Y-P-C* 297 R-F-Pen*-Kt-G-H-F-G-IDAt-NMeL-Y-P-C* 298 R-F-Pen*-T-G-H-X7N-G-Sar-NMeL-Y-P-C* 299 K -F-Pcn*-I< -G-X6'-F-G-Sar-NMcE -Y-P-C* 300 R-F-Pen*-T-G-H-X70-G-Sar-NMeL-Y-P-C* 301 R-F-Pen*-T-G-H-X7Q-G-Sar-NMeL-Y-P-C* 302 R-F-Pen*-T-G-X6S-F-G-Sar-NMeL-Y-P-C* 303 I< -F-Pcn*-I< -G-X6'-F-G-X5,' -NMcL-Y-P-C* 304 R-F-Pen*-T-G-X6T-F-G-Sar-NMeL-Y-P-C* 305 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12D-C* 306 R-F-Pen*-T-G-H-Y-G-Sar-NMeL-Y-P-C* 307 R-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 308 (D-Arg)-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y- P-C*

[1082] 309 R-F-Pen*-T-G-X6U-F-G-Sar-NMeL-Y-P-C* 310 X1A-Pen*-X4Y-G-H-F-G-Sar-NMeL-Y-P-C* 311 X1A-F-Pen*-Et-G-X6C-F-G-X9Mt-NMeL-Y-P-C* 312 N-F-Pen*-T-G-H-F-G-IDA-NMeL-Y-P-C* 313 R-F-Pen*-T-G-H-X7R-G-Sar-NMeL-Y-P-C* 314 [< -X2' '-Pcn*-I< -G-H-F-G-Sar-NMcE -Y-P-C* 315 X1A-F-Pen*-Et-G-H-F-G-Sar-X10At-Y-P-C* 316 F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 317 F-Pen*-T-G-H-F-G-X9N-NMeL-Y-P-C* 318 I< -F-Pcn*-I< -G-X6'-F-G-X9,-NMcE -Y-P-C* 319 Xl'-F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 320 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12E-C* 321 X1D-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 322 I< -F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 323 (D-Arg)-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 324 R-F-Pcn*-D -G-H-F-G-Sar-NMcK -Y-P-C* 325 R-F-Pen*-T-G-H-X7S-G-Sar-NMeL-Y-P-C* 326 R-F-Pen*-T-G-X6V-F-G-Sar-NMeL-Y-P-C* 327 F-Pen*-X4D-G-H-F-G-Sar-NMeL-Y-P-C* 328 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Xllc-P-C* 329 X2B-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 330 R-F-Pen*-T-G-H-X7T-G-Sar-NMeL-Y-P-C* 331 R-F-Pen*-T-G-H-X7U-G-Sar-NMeL-Y-P-C* 332 R-F-Pen*-T-G-H-F-G-Sar-NMeL-X11D-P-C* 333 R-F-Pen*-T-G-H-X7V-G-Sar-NMeL-Y-P-C* 334 R-F-Pen*-T-G-H-X7W-G-Sar-NMeL-Y-P-C* 335 R-F-Pen*-K-G-H-F-G-Sar-NMeE-Y-P-C* 336 Xl l5-F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 337 R-F-Pen*-T-G-X6ZA-F-G-Sar-NMeL-Y-P-C* 338 Xl'-F-Pcn*-I< -G-H-F-G-X9,,-NMcE -Y-P-C* 339 R-F-Pen*-T-G-H-X7X-G-Sar-NMeL-Y-P-C* 340 R-F-Pen*-T-G-H-X7Y-G-Sar-NMeL-Y-P-C* 341 F-Pen*-T-G-H-F-G-X9P-NMeL-Y-P-C* 342 N-F-Pcn*-E -G-H-F-G-Sar-NMcK -Y-P-C* 343 Xl l,-F-Pcn*-I< -G-H-F-G-Sar-NMcE -Y-P-C* 344 R-F-Pen*-T-G-H-X7Z-G-Sar-NMeL-Y-P-C* 345 Pcn*-K -G-H-F-G-Sar-NMcE -Y-P-C* 346 R-F-Pen*-T-G-H-X7AA-G-Sar-NMeL-Y-P-C* 347 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12F-C* 348 R-F-Pen*-T-G-H-X7AV-G-Sar-NMeL-Y-P-C* 349 R-F-Pen*-K-G-H-F-G-Sar-NMeD-Y-P-C* 350 X|,-F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 351 N-F-Pcn*-I< -G-H-F-G-X9' -NMcL-Y-P-C* 352 R-F-Pcn*-E -G-H-F-G-Sar-K -Y-P-C* 353 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12G-C* 354 R-F-Pen*-T-G-H-X7L-G-Sar-NMeL-Y-P-C* 355 X2C-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 356 R-F-Pen*-T-G-H-F-G-IDA-NMeL-Y-P-C*

[1083]

[1084] 357 X1A-F-Pen*-X4Y-G-H-F-G-Sar-NMeL-Y-P-C* 358 R-F-Pen*-T-G-X6W-F-G-Sar-NMeL-Y-P-C* REF REF

[1085] ID Sequence ID Sequence

[1086] NO: NO:

[1087] 359 R-F-Pen*-T-G-X6X-F-G-Sar-NMeL-Y-P-C* 360 R-F-Pen*-T-G-X6ZB-F-G-Sar-NMeL-Y-P-C* 361 F-Pcn*-I< -G-H-F-G-Xl<-NMcE -Y-P-C* 362 Xl'-F-Pcn*-I< -G-H-F-G-Sar-E -Y-P-C* 363 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12H-C* 364 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12A-C* 365 X1A-F-Pen*-X4D-G-H-F-G-Sar-NMeL-Y-P-C* 366 R-F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 367 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12I-C* 368 L-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 369 (D-Leu)-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y- 370 R-F-Pen*-T-G-X6Y-F-G-Sar-NMeL-Y-P-C* P-C*

[1088] 371 R-F-Pen*-T-G-H-X7AB-G-Sar-NMeL-Y-P-C* 372 R-F-Pen*-T-G-X6Z-F-G-Sar-NMeL-Y-P-C* 373 XI A-F-Pcn*-E -G-H-F-G-Sar-NMcI< -Y-P-C* 374 R-F-Pcn*-E -G-H-F-G-X, |-NMcL-Y-P-C* 375 N-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 376 R-F-Pen*-T-G-X6AA-F-G-Sar-NMeL-Y-P-C* 377 R-F-Pen*-T-G-H-X7AC-G-Sar-NMeL-Y-P-C* 378 R-F-Pen*-T-G- X6C-F-G-Sar-NMeL-Y-P-C* 379 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-P-C* 380 X1A-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 381 R-F-Pen*-T-G-X6AB-F-G-Sar-NMeL-Y-P-C* 382 F-PciF-K -G-H-F-G-X ' -NMcE -Y-P-C* 383 R-F-Pen*-T-G-H-X7AD-G-Sar-NMeL-Y-P-C* 384 R-F-Pen*-T-G-H-F-G-X9R-NMeL-Y-P-C* 385 R-F-Pen*-T-G-H-X7AE-G-Sar-NMeL-Y-P-C* 386 R-F-Pen*-T-G-X6AC-F-G-Sar-NMeL-Y-P-C* 387 R-F-Pen*-T-G-H-X7AF-G-Sar-NMeL-Y-P-C* 388 (D-Asn)-(D-Phe)-Pen*-T-G-H-F-G-Sar-NMeL-Y- P-C*

[1089] 389 R-F-Pen*-T-G-H-X7AG-G-Sar-NMeL-Y-P-C* 390 R-F-Pen*-X4D-G-H-F-G-Sar-NMeL-Y-P-C* 391 F-Pen*-T-G-H-F-G-X9S-NMeL-Y-P-C* 392 R-F-Pen*-T-G-X6AD-F-G-Sar-NMeL-Y-P-C* 393 R-F-Pen*-T-G-H-F-G-X9S-NMeL-Y-P-C* 394 R-F-Pen*-X4B-G-X6D-F-G-Sar-NMeL-Y-P-C* 395 R-F-Pen*-T-G-H-F-G-Sar-NMeL-Y-X12I-C* 396 R-F-Pen*-T-G-X6AE-F-G-Sar-NMeL-Y-P-C* 397 R-F-Pen*-T-G-X6AF-F-G-Sar-NMeL-Y-P-C* 398 R-F-Pcn*-E -G-X4l,-F-G-X9 l-NMcL-Y-P-C* 399 Xl'-F-Pcn*-E -G-X9l,-F-G-X9 l-NMcL-Y-P-C* 400 Xl'-F-Pcn*-Xl' -G-X6' -F-G-Sar-NMcE -Y-P-C* 401 R-F-Pen*-T-G-X6AG-F-G-Sar-NMeL-Y-P-C* 402 R-F-Pen*-T-G-X6AH-F-G-Sar-NMeL-Y-P-C* 403 R-F-Pen*-T-G-X®-X7AE-G-Sar-NMeL-Y-P-C* 404 X1A-F-Pen*-Et-G-X®-F-G-Sar-NMeKt-Y-P-C* 405 N-F-Pcn*-E -G-X6l,-F-G-Sar-NMcI< -Y-P-C* 406 Xl'-F-Pcn*-E -G-X6' -F-G-Sar-NMcI< -Y-P-C* 407 N-F-Pcn*-E -G-X6' -F-G-IDA-NMcI< -Y-P-C* 408 R-F-Pen*-T-G-X6C-X7AE-G-Sar-NMeL-Y-P-C* 409 N-F-Pcn*-E -G-X'l,-F-G-IDA-NMcI< -Y-P-C* 410 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P- Pen*

[1090] 411 Xl'-F-Pcn*-E -G-X6l,-F-G-IDA-NMcI< -Y-P-C* 412 X1A-F-Pen*-X4At-G-X6C-X7AH-G-IDA-NMeEt-Y- P-C*

[1091] 413 Xl''-F-Pcn*-Xl'' -G-X'4,-Xl l-G-Sar-NMcE -Y-P- 414 I< -F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P-C*

[1092] C*

[1093] 415 R-F-Pen*-T-G-X6AI-F-G-Sar-NMeL-Y-P-C* 416 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-X12K-C* 417 Xl''-F-Pcn*-Xl'' -G-X6' -X, i-G-IDA-NMcE -Y-P- 418 X1A-F-Pen*-X4At-G-X6C-X7AI-G-IDA-NMeEt-Y-P- C* C*

[1094] 419 X1A-F-Pen*-X4At-G-X6C-X7AE-G-IDA-NMeEt-Y- 420 X1A-F-Pen*-X4At-G-X6AJ-F-G-IDA-NMeEt-Y-P- P-C* C*

[1095] 421 X1A-F-Pen*-X4At-G-X6C-X7AJ-G-Sar-NMeEt-Y-P- 422 X1A-F-Pen*-X4At-G-X6AK-F-G-IDA-NMeEt-Y-P- C* C*

[1096] 423 Xl'-F-Pcn*-Xlz-G-X6' -F-G-IDA-NMcI< -Y-P-C* 424 X1A-F-Pen*-X4At-G-X6D-X7AK-G-Sar-NMeEt-Y-P- C*

[1097] 425 X1A-F-Pen*-X4At-G-X6C-X7AL-G-IDA-NMeEt-Y- 426 X1A-F-Pen*-Et-G-X6C-X7AE-G-IDA-NMeKt-Y-P- P-C* C*

[1098] 427 Xl'-F-Pcn*-Xl' -G-X6'l-F-G-IDA-NMcE -Y-P- 428 R-F-Pen*-T-G-X6AM-F-G-Sar-NMeL-Y-P-C*

[1099] C*

[1100] 429 Xl'-F-Pcn*-Xl' -G-X6' -F-G-IDA-NMcE -Y-P- 430 X1A-F-Pen*-X4At-G-X6C-X7AM-G-IDA-NMeEt-Y- C* P-C*

[1101] 431 Xl'-F-Pcn*-Xl' -G-X6' -X '-G-IDA-NMcE -Y-P- 432 X1A-F-Pen*-X4At-G-X6C-X7AN-G-IDA-NMeEt-Y- C* P-C*

[1102] 433 Xl'-F-Pcn*-Xl' -G-X6',,-F-G-IDA-NMcE -Y-P- 434 I< -F-Pcn*-Xl' -G-X6' -F-G-Sar-NMcE -Y-P-C*

[1103] C*

[1104] 435 Xl''-F-Pcn*-Xl' -G-X6'l'-F-G-IDA-NMcE -Y-P- 436 N-X2A-Pen*-Et-G-X6D-F-G-Sar-NMeKt-Y-P-C*

[1105] C*

[1106] 437 N-F-Pcn*-E -G-X6' -F-G-Sar-NMcI< -Y-P-C* 438 X1A-F-Pen*-X4At-G-X6C-X7AO-G-IDA-NMeEt-Y- P-C*

[1107]

[1108] 439 R-F-Pen*-T-G-X6D-F-G-Sar-NMeL-Y-X12L-C* 440 R-F-Pen*-T-G-X6AQ-F-G-Sar-NMeL-Y-P-C* REF REF

[1109] ID Sequence ID Sequence

[1110] NO: NO:

[1111] 441 XI A-F-Pcn*-XIA-G-X6AI<-F-G-IDA-NMcE -Y-P- 442 XI A-F-Pcn*-XIA-G-X6' -X "-G-Sar-NMcE -Y-P- C* C*

[1112] 443 XI A-F-Pcn*-XIA-G-X6AS-F-G-IDA-NMcE -Y-P- 444 XI A-F-Pcn*-XIA-G-X6AI-F-G-IDA-NMcE -Y-P- C* C*

[1113] 445 XI A-F-Pcn*-XIA-G-X6' -Xl'-G-IDA-NMcE -Y-P- 446 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-X12M-C*

[1114] C*

[1115] 447 XI A-F-Pcn*-XIA-G-X6' -XAI'-G-IDA-NMcE -Y- 448 R-F-Pen*-T-G-X6AU-F-G-Sar-NMeL-Y-P-C*

[1116] P-C*

[1117] 449 XI A-F-Pcn*-XIA-G-X6A-F-G-IDA-NMcE -Y-P- 450 XI A-F-Pcn*-XIA-G-X6AI-F-G-IDA-NMcE -Y-P- C* C*

[1118] 451 R-F-Pen*-T-G-X6AW-F-G-Sar-NMeL-Y-P-C* 452 XI A-F-Pcn*-XIA-G-XAI,-XA I-G-Sar-NMcE -Y-P- C*

[1119] 453 XI A-F-Pcn*-XIA-G-X6''-XAK-G-Sar-NMcE -Y-P- 454 XI A-F-Pcn*-XIA-G-X6AA-F-G-IDA-NMcE -Y-P- C* C*

[1120] 455 X1A-F-Pen*-X4At-G-X6C-X7A(2-G-IDA-NMeEt-Y- 456 XI A-F-Pcn*-XIA-G-X6AY-F-G-IDA-NMcE -Y-P- P-C* C*

[1121] 457 XI A-F-Pcn*-XIA-G-X6AZ-F-G-IDA-NMcE -Y-P- 458 X1A-F-Pen*-X4At-G-X®-X7AR-G-IDA-NMeEt-Y- C* P-C*

[1122] 459 R-F-Pen*-T-G-X®A-F-G-Sar-NMeL-Y-P-C* 460 XI A-F-Pcn*-XIA-G-X6' -XAS-G-IDA-NMcE -Y- P-C*

[1123] 461 R-F-Pen*-T-G-X®-F-G-Sar-NMeL-Y-X12N-C* 462 XI A-F-Pcn*-XIA-G-X6l,-XAI-G-IDA-NMcE -Y- P-C*

[1124] 463 R-F-Pen*-T-G-X6BB-F-G-Sar-NMeL-Y-P-C* 464 XI A-F-Pcn*-XIA-G-X6l,-XAI-G-IDA-NMcE -Y- P-C*

[1125] 465 F-Pen*-T-G-H-F-G-X90-NMeL-Y-P-C* 466 R-F-Pen*-Et-G-X®-F-G-Sar-NMeKt-Y-P-C* 467 X1A-F-Pen*-Kt-G-X6C-F-G-Sar-NMeEt-Y-P-C* 468 F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-X120-C* 469 R-F-Pen*-T-G-X®D-F-G-Sar-NMeL-Y-P-C* 470 I< -F-Pcn*-XIIJ-G-H-F-G-Sar-NMcL-Y-P-C* 471 F-Pen*-T-G-H-F-G-X9R-NMeL-Y-P-C* 472 F-Pen*-Kt-G-H-F-G-X9S-NMeEt-Y-P-C* 473 I< -F-Pcn*-T-G-H-F-G-X9s-NMcL-Y-P-C* 474 I< -F-Pcn*-T-G-H-F-G-X9l<-NMcL-Y-P-C* 475 F-Pen*-Et-G-H-F-G-Sar-NMeKt-Y-P-C* 476 R-X2E-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 477 N-F-Pen*-Kt-G-X6A-F-G-IDA-NMeEt-Y-P-C* 478 D-F-Pen*-Kt-G-H-F-G-Sar-NMeEt-Y-P-C* 479 Xl'-F-Pcn*-E -G-H-F-G-X9 l-NMcL-Y-P-C* 480 N-F-Pen*-Kt-G-H-F-G-IDA-NMeEt-Y-P-C* 481 F-Pen*-Kt-G-X6A-F-G-Sar-NMeEt-Y-P-C* 482 X1A-F-Pen*-Kt-G-X6A-F-G-IDA-NMeEt-Y-P-C* 483 X1A-F-Pen*-Kt-G-X6A-F-G-Sar-NMeEt-Y-P-C* 484 X1A-F-Pen*-Kt-G-X6D-F-G-Sar-NMeEt-Y-P-C* 485 X1A-F-Pen*-Kt-G-H-F-G-X9R-NMeEt-Y-P-C* 486 N-F-Pcn*-E -G-EI-F-G-X9 l-NMcL-Y-P-C* 487 Xl'-F-Pcn*-Xl' -G-H-F-G-Sar-NMcE -Y-P-C* 488 N-F-Pen*-Kt-G-X6A-F-G-Sar-NMeEt-Y-P-C* 489 X1A-F-Pen*-X4At-G-H-F-G-IDA-NMeEt-Y-P-C* 490 XI A-F-Pcn*-XIA-G-E[-F-G-X9A-NMcL-Y-P-C* 491 Kl-X2AA-Pen*-Kt-G-X-F-G-X9O-NMeEt-Y-P-C*t 492 X1A-F-Pen*-Kt-G-H-F-G-IDA-NMeEt-Y-P-C* 493 H-Pcn*-K -G-EI-F-G-Sar-NMcE -Y-P-C* 494 (D-His)-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 495 N-F-Pcn*-XIA-G-EI-F-G-IDA-NMcE -Y-P-C* 496 X1A-Pen*-T-G-H-F-G-Sar-NMeL-Y-P-C* 497 N-F-Pen*-Kt-G-H-F-G-IDA-NMeKt-Y-P-C* 498 XI A-F-Pcn*-E -G-EI-F-G-IDA-NMcI< -Y-P-C* 499 N-F-Pcn*-E -G-EI-F-G-IDA-NMcI< -Y-P-C* 500 R-F-Pen*-T-(D-Val)-H-F-G-Sar-NMeL-Y-P-C* 501 XAA-X2A-Pcn*-XkA-G-X6A-F-G-Sar-NMcE -Y-P- 502 N-X2A-Pcn*-E -G-X6' -F-G-Sar-NMcI< -Y-P-C*

[1126] C*

[1127] 503 XI A-F-Pcn*-XllA-G-XAI,-F-G-IDA-NMcK -Y-P- 504 X1A-F-Pen*-X4At-G-X6C-F-G-KDA-NMeEt-Y-P- C* C*

[1128] 505 N-X2A-Pen*-X4At-G-X®-F-G-Sar-NMeEt-Y-P-C* 506 N-X2A-Pen*-X4At-G-X6C-F-G-Sar-NMeEt-Y-P-C* 507 N-F-Pcn*-XIA-G-EI-F-G-Sar-NMcE -Y-P-C* 508 N-F-Pcn*-E -G-EI-F-G-Sar-XluA-Y-P-C* 509 R-F-Pen*-X4E-G-H-F-G-Sar-NMeL-Y-P-C* 510 R-F-Pen*-X4F-G-H-F-G-Sar-NMeL-Y-P-C* 511 R-F-Pen*-X4G-G-H-F-G-Sar-NMeL-Y-P-C* 512 K -F-Pcn*-I<-G-E[-F-G-Sar-NMcL-Y-P-C* 513 N-X2A-Pcn*-E -G-EI-F-G-Sar-NMcI< -Y-P-C* 514 F-Pcn*-I< -G-X6A-F-G-X9l<-NMcE -Y-P-C* 515 XI A-F-Pcn*-XIA-G-X6l',l-F-G-IDA-NMcE -Y-P-

[1129]

[1130] C*

[1131] wherein:

[1132] Pen is penicillamine, Sar is sarcosine, NMeL is A'-mcthyl-lcucinc. NMeD is A'-mcthyl-aspartic acid, NMeE is A'-mcthyl-glutamic acid, NMeK is A'-mcthyl-lysinc. and IDA is iminodiacetic acid; each of X1A, X1B, X1C, and X1Dis a lysine replacement that is:

[1133]

[1134] each of X2A, X2B, X2C, X2D, and X2Eis a phenylalanine replacement that is:

[1135]

[1136] each of X4A, X4B, X4C, X4D, X4E, X4F, and X4Gis a lysine replacement that is:

[1137]

[1138] HO^Oo<VOHo o

[1139] H. N^ yrJNy^0HH2N^^^ty)i4

[1140] i n HK Z14

[1141] c / xDH O^OH °

[1142] X4EX4F

[1143] O^OH

[1144] H / xH / \HZl\

[1145] 0 0 0

[1146] O^OH

[1147]

[1148] X4G

[1149] each of X4Yand X4Zis an other amino acid that is:

[1150] each of X6AX^c X^ X^^ X^ X^ X^ X^ X^ X^ X^^ X^ X^Q X^

[1151] , A, yx., yx.?yx.?yx.?yx., yx., yx., yx., yx.,

[1152]

[1153] A?yx?yx?yx, yx, yx, yx, yx, yx, yx, yx, yx, yx, yx, yx, yx, yx, X6BC5X6BD, and X6BEis a histidine replacement that is:

[1154] NxMeO^ x^

[1155] rj JL Ji T ii L N XA^N

[1156] H2N\OHH2NA0HH2NYHH2NVH0 0 0 0 X6AX6BX6CX6D

[1157] 1

[1158] MeO^^\ / H2N\X^X, T H T T ii T H T ii X-A^NXA^NXA^N H2N'YHH2N\OHFEN-V™ H2NY°H0 0 0 0 X6EX6FX6GX6HI^^NH

[1159] I

[1160] °^x^

[1161] T ii

[1162] XA T ^ iNi N XA^N.xA^

[1163] H. N-Y™ H2N\OHA " H2N-YOH0 0 o 0

[1164]

[1165] X61X6JX6KX6L 0

[1166] H H T T ii \ / I==

[1167] 1 T ii / A^N

[1168] < > o rX X<° vjv_ ° H2NVHH2N'\OHH2NVHz '

[1169] 0 o 0 I 0 ^6M X6NX60X6P

[1170] H

[1171] , N

[1172] N=X \ II rr 5— X^-OH

[1173] X / OH \ H2N\™ H2NYOHH2N-*YOHH2N y \=^ / 0 0 0 0

[1174] X6QX6RX6SX6T

[1175] 1

[1176] N^.0^ N=\ ° r> r II L.N~~ / N-S'°

[1177] \

[1178] H2N'\OHH2NV " H2NXY°HH2NY0H0 0 0 0 X6UX6V^6W x6X

[1179] NC^N

[1180] Tj X P H)

[1181] H2NYHNKV H2N-YOH

[1182] 0 0 0

[1183] X6YX6Z^6AA

[1184] N-NH H H X

[1185] Y^N HN- /

[1186] JL JJ

[1187] H2N\OHnr. VH° H2NVHH2NY0H0 0 0 0 ^6AC ^6AD ^6AE ^6AFXN" AXN-^ S'A L. N > A / N

[1188] A, NH2NYHH2N-V0HH2NVH0 0 0 0 ^6AG ^6 AH X6AI^6AJ

[1189] N 1 '?

[1190] 1 II \ 11 T ii X OH 1

[1191] H2N y H2NY0HH2N\OHH2N'Y)H0 0 0 0 ^6AK ^6 AL AM ^6 AN

[1192]

[1193] L if

[1194] H2N-VOHH2N\OHH2N\

[1195] 0 0 00H^6AP ^6AQ ^6 AR

[1196] Cl

[1197] CI\^N

[1198] T T HFAO HA / YOHH:AYOHH2N'V, HH2NA0H

[1199] 0 0 0 0 ^6AS X6AT^6AU ^6AV

[1200] OH OH H

[1201] F3%N

[1202] J^ / NHT ii

[1203] >0 H2NVHH2N\'OHH2N-YOHH2N0OH0 0 0 0 ^6AW ^6 AX ^6AY ^6 AZ

[1204] °v\

[1205] HN-^ HN-\,

[1206] L N T H

[1207] H2N\OHH2N-1YOHH. N^ n H2NO°H0 \ / 1=0 0 0 ^6BA ^6BB ^6BC ^6BD vj_v °

[1208] H / \ riO

[1209] z

[1210] I CX I T I N

[1211] H2N'YW

[1212] 0

[1213] ^6BE

[1214]

[1215] each of X6ZAand X6ZBis a lysine replacement that is:

[1216]

[1217] each of X7A, X7B, X7C, XTO, X7E, XA X7G, X™, X71, X7J, XA X7L, X, X7N, X70, X7P, X7Q, X, ■V? S -v7T -v7U -v7V v7W - r7X rl rlZ v7AA -v7AB v^AC v7AD v^AE -v7AF -v7AG -v7AH v^AI -v7AJ v7AK x., x., x., x., x., Jx., Jx., x., x., x., x., x., x., x., x.,X7AL,X7AM.X7AN,X7AO,X7AP,X7AQ,X7ARX7AS,X7AT,X7AUX7AVa p|qeny|a|an|nereplacement that

[1218]

[1219] is: MeOyjx \

[1220] Tj ry^N- xo. HA0HH2N-YOHH2N\OHH2NYH

[1221] 0 0 0 0 X7AX7BX7CX7D\

[1222] XVN~

[1223] CM X

[1224] Z ^0 H2N\0HH2N\OHH2N

[1225] 0 0=\

[1226] / \1 OHXO 4. n o 0 7E x^ o= \ v — / ' X7HOH M C z

[1227] I

[1228] vjO '■... JO I

[1229] 2O U_

[1230] H NV H^V T H2N-Y

[1231] roHH2NX0H0 0 / \Tz 0 0 X71X7V. / ) OJX7KX7LO X \ / = V—

[1232] H OH

[1233] ^o=\ H H N v c oN N

[1234] M C z -0 \ / I _

[1235] I

[1236] o o ^ £< 3 \ I

[1237] H2NVHH2N^OHH2N^OH0 0 0 T 0

[1238] 7Mx™70K>

[1239] X X z X7PH

[1240] ^° \ JLX y-OH 13 o 7

[1241] \ / i _ o - H2N-*YOHH2N\OHI 0 0

[1242] X7QX7S

[1243] H

[1244] ^^NH2

[1245] on

[1246] I °\

[1247] H2N^YOHH2N\OHH. N’X " o 0 0 X7UX7Vx7XF

[1248] xsxs FTA £3 o H2N^YOHH2N\OHH. N-Y™ H2N-*YOH0 0 0 0

[1249]

[1250] X7YX7ZX7AAX7AB H

[1251] N I JYA

[1252] o X^X)H

[1253] H2N Y°H / ° Y H2NJY0HH2NYHY 0 0 0 0 X7ACX7ADX7AEX7AF

[1254] 1

[1255] o

[1256] I I T XI jn>—

[1257] H^XX H2N\OHH2N\OHH2NJY0H0 0 TZ o 0 X7AGX7AHX7AIX7AJHCk ^ o

[1258] Xj O

[1259] w xx XX /

[1260] HZ¥°HH2N\OHTZ H2NYHH2NYH0 0 >° o * 0 0 X7AKX7ALT X? AM X? AN

[1261] o

[1262] o

[1263] T XX

[1264] H2fZyOHH. N-Y™ H2fZY°HH2N^YH0 0 0 0 X7A0X7APX7AQX7ARH N

[1265] Y 0

[1266] H. N-Y™ H2NVHH. N-Y™ H2N<^OHo 0 0 0

[1267]

[1268] X7ASX7ATX7AUX7AVeach of X^ X^ X^ X^ X^ X^ X^ X^ X^ X^ X^^ X^O X^P X^Q X^ and X9S, is a sarcosine replacement that is:

[1269] Y oH™AHX9C

[1270] OH OH

[1271] 0 o^X -''' O

[1272] n^ oH

[1273]

[1274] X’DX" OH OH OH OH OH

[1275] J J

[1276] 0 o^ y 0 FsC^ 0

[1277] ™YOHHN^OH X9GX" X” OH 0

[1278] H

[1279] F3C^> 0 HO^^^i 0

[1280] °=< Y i ftH^-A0H™Y0HO-N HN^QHX9JX»K X9L0 H ft H ft 'f'O^x^N^ X)H

[1281] 'z2 \z4

[1282] ^9M X9NX90H ft 0

[1283] 'f'Ox^x)'N^x^OH - 'z3HH^ OH

[1284] X9PX9Q

[1285] Y NH Iu uo o I N^0H

[1286] 0 0 0

[1287] X9R

[1288] CK / OH

[1289] Y NH I |, |, o o0

[1290] 0 0 0

[1291]

[1292] X9S

[1293] NH2

[1294] X10Ais a lysine replacement that i

[1295]

[1296] s O

[1297] each of X11A, X11B, X11C, and X11Dis a tyrosine replacement that is:

[1298]

[1299] and each of X12A, X12B, X12C, X12D, X12E, X12F, X12G, X12H, X121, X12J, X12K, X12L, X12M, X12N, and

[1300]

[1301]

[1302] * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink;

[1303] t denotes crosslinked amino acids connected to each other via an X4-X9crosslink or an X4-X10crosslink; and

[1304] * denotes crosslinked amino acids connected to each other via an X’-X13crosslink.

[1305]

[0241] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[1306] X1-F-Pen*-T-G-X6-X7-G-X9-NMeL-Y-P-C* (REF ID NO: 27),

[1307] wherein:

[1308] Pen is penicillamine and NMeL is JV-methyl-leucine;

[1309] X1is arginine (R), asparagine (N), or leucine (L), or is absent;

[1310] X6is histidine (H) or a histidine replacement;

[1311] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement; X9is sarcosine (Sar) or a sarcosine replacement; and

[1312] * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink.

[1313]

[0242] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[1314] Xl-F-Pcn*-X4:-G-Xfi-X7-G-X9'-NMcL-Y-P-C* (REF ID NO: 28), wherein:

[1315] Pen is penicillamine and NMeL is JV-methyl-leucine;

[1316] X1is arginine (R), asparagine (N), or leucine (L), or is absent;

[1317] X4is lysine (K) or a lysine replacement;

[1318] X6is histidine (H) or a histidine replacement;

[1319] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement; X9is a sarcosine replacement; * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink; and t denotes crosslinked amino acids connected to each other via an X4-X9crosslink.

[1320]

[0243] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[1321] X1-F-Pen*-X4t-G-X6-X7-G-X9-X10t-Y-P-C* (REF ID NO: 29),

[1322] wherein:

[1323] Pen is penicillamine;

[1324] X1is arginine (R), asparagine (N), or leucine (L), or is absent;

[1325] X4is lysine (K) or a lysine replacement;

[1326] X6is histidine (H) or a histidine replacement;

[1327] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement; X9is sarcosine (Sar) or a sarcosine replacement;

[1328] X10is '-mcthy I -aspartic acid (NMeD) or A'-mcthy I -glutamic acid (NMeE);

[1329] * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink; and t denotes crosslinked amino acids connected to each other via an X4-X10crosslink.

[1330]

[0244] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[1331] Xli-F-Pcir!-TG-X' -X7-G-X"-NMcL-Y-P-C*i(REF ID NO: 30),

[1332] wherein:

[1333] Pen is penicillamine and NMeL is JV-methyl-leucine;

[1334] X1is lysine (K) or a lysine replacement;

[1335] X6is histidine (H) or a histidine replacement;

[1336] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement; X9is sarcosine (Sar) or a sarcosine replacement;

[1337] * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink; and * denotes crosslinked amino acids connected to each other via an X’-X13crosslink.

[1338]

[0245] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises the following amino acid sequence:

[1339] Xlt-F-Pen*-X4t-G-X6-X7-G-X9-X10t-Y-P-C*t(REF ID NO: 31),

[1340] wherein:

[1341] Pen is penicillamine;

[1342] X1is lysine (K) or a lysine replacement;

[1343] X4is lysine (K) or a lysine replacement;

[1344] X6is histidine (H) or a histidine replacement;

[1345] X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement; X9is sarcosine (Sar) or a sarcosine replacement;

[1346] X10is A'-mcthy I -aspartic acid (NMeD) or A'-mcthy I -glutamic acid (NMeE)

[1347] * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink; t denotes crosslinked amino acids connected to each other via an X4-X10crosslink; and

[1348] * denotes crosslinked amino acids connected to each other via an X’-X13crosslink.

[1349]

[0246] In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises an amino acid sequence having at least 80% sequence identity with any one of REF ID NOs: 3-985. In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises an amino acid sequence having at least 85% sequence identity with any one of REF ID NOs: 3-985. In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises an amino acid sequence having at least 90% sequence identity with any one of REF ID NOs: 3-985. In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises an amino acid sequence having at least 95% sequence identity with any one of REF ID NOs: 3-985. In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises an amino acid sequence having at least 98% sequence identity with any one of REF ID NOs: 3-985. In certain embodiments, the cyclic peptide or pharmaceutically acceptable salt thereof comprises an amino acid sequence having 100 % sequence identity with any one of REF ID NOs: 3-985.

[1350]

[0247] In some embodiments, a cyclic peptide (of any sequence provided herein) comprises one or more amino acid substitutions, additions, or deletions as described herein, in any combination.

[1351]

[0248] In certain embodiments, an amino acid sequence provided herein includes 0, 1, 2, 3, 4, or 5 amino acid substitutions. In certain embodiments, an amino acid sequence provided herein includes 1 substitution. In certain embodiments, an amino acid sequence provided herein includes 2 substitutions. In certain embodiments, an amino acid sequence provided herein includes 3 substitutions. In certain embodiments, an amino acid sequence provided herein includes 4 substitutions. In certain embodiments, an amino acid sequence provided herein includes 5 substitutions.

[1352]

[0249] In certain embodiments, an amino acid sequence herein includes 0, 1, 2, 3, 4, or 5 amino acid additions. In certain embodiments, an amino acid sequence provided herein includes 1 addition. In certain embodiments, an amino acid sequence provided herein includes 2 additions. In certain embodiments, an amino acid sequence provided herein includes 3 additions. In certain embodiments, an amino acid sequence provided herein includes 4 additions. In certain embodiments, an amino acid sequence provided herein includes 5 additions.

[1353]

[0250] In certain embodiments, an amino acid sequence herein includes 0, 1, 2, 3, 4, or 5 amino acid deletions. In certain embodiments, an amino acid sequence provided herein includes 1 deletion. In certain embodiments, an amino acid sequence provided herein includes 2 deletions. In certain embodiments, an amino acid sequence provided herein includes 3 deletions. In certain embodiments, an amino acid sequence provided herein includes 4 deletions. In certain embodiments, an amino acid sequence provided herein includes 5 deletions.

[1354]

[0251] In certain embodiments, the N-terminus of the cyclic peptide is acylated (denoted by “Ac-” at the N-terminus of an amino acid sequence). In certain embodiments, the C-terminus of the cyclic peptide is amidated, i. e., the traditional C-terminal -C(=O)OH is replaced with -C(=O)NH2 (denoted by “-NH2” at the C-terminus of an amino acid sequence) or -C(=O)NH- (denoted by “-NH-” at the C-terminus of an amino acid sequence). In certain embodiments, a cyclic peptide provided herein comprises an acylated N-terminus and an amidated C-terminus. In certain embodiments, the amidated C-terminus of the cyclic peptide is of formula -C(=O)NH(CH2)4N(CH3)3+.

[1355]

[0252] In certain embodiments, a cyclic peptide or dimer further comprises one or more lipid groups (e.g., one lipid group). In certain embodiments, the N-terminus of the cyclic peptide is acylated with a lipid group. In certain embodiments, each lipid group independently comprises one or more of the following in any combination:

[1356]

[1357]

[0253] In certain embodiments, each lipid group is or comprises the formula:

[1358]

[1359] wherein n2 is 0, 1, 2, 3, or 4. In certain embodiments, each lipid group is or comprises the formula:

[1360]

[1361]

[0254] In certain embodiments, each lipid group is independently of formula:

[1362]

[1363]

[1364]

[1365]

[1366]

[1367] In certain embodiments, each lipid group is

[1368]

[1369] Covalent Binding Moieties

[1370]

[0255] Cyclic peptides described herein may further comprise the group -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety. “Covalent binding moiety” as used herein refers to a chemical group capable of reacting with an amino acid residue of a target protein (e.g., FcRn) to form a covalent bond. Examples of covalent binding moieties are known in the art (often referred to as “covalent warheads”). Examples of covalent binding moieties can be found in, e.g., “The future of covalent drugs” C& EN Discovery Report, Q32022, pp. 1-20; Gehringer, M. and Laufer, S. A. “Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology” J. Med. Chem. 2019, 62, 5673-5724; and Abranyi-Balogh, P. and Keserii, G. M. “Warheads for designing covalent inhibitors and chemical probes” A dvances in Chemical Proteomics 2022, chapter 2, pp. 47-73, each of which are incorporated herein by reference in their entireties.

[1371]

[0256] In certain embodiments, the cyclic peptide further comprises the group -L’-Rw, wherein L1is a bond or a linker, and Rwis a covalent binding moiety. In certain embodiments, a covalent binding moiety comprises a chemical group capable of reacting with an amine (e.g., on a lysine residue of the target protein). In certain embodiments, a covalent binding moiety comprises a chemical group capable of reacting with a thiol (e.g., a cysteine residue of the target protein). In certain embodiments, the covalent binding moiety (z. e., Rw) is a covalent binding moiety comprising a vinyl sulfone, a sulfonyl halide, a squarate, or a benzaldehyde.

[1372]

[0257] In certain embodiments, Rwcomprises a squarate. In certain embodiments, Rwis a squarate. In certain embodiments, Rwis of Formula (i):

[1373] Rw1z.x

[1374]

[1375] (i),

[1376] wherein Rwlis optionally substituted Ci-6 alkyl. In certain embodiments, Rwlis unsubstituted Ci-6 alkyl. In certain embodiments, Rwlis unsubstituted Ci-6 alkyl. In certain embodiments, Rwlis methyl.

[1377] CkyO

[1378]

[0258] In certain embodiments, Rwis:

[1379]

[1380] OMe

[1381]

[0259] In certain embodiments, Rwcomprises a sulfonyl halide. In certain embodiments, Rwis a sulfonyl halide. In certain embodiments, Rwis of Formula (ii):

[1382] c \> W p /

[1383] RW2

[1384]

[1385] (ii),

[1386] wherein Rw2is halogen or a leaving group. In certain embodiments, Rw2is halogen. In certain embodiments, Rw2is F.

[1387] O 0

[1388]

[0260] In certain embodiments, Rwis:

[1389]

[1390] ^-

[0261] In certain embodiments, Rwcomprises a vinyl sulfone. In certain embodiments, Rwis a vinyl sulfone. In certain embodiments, Rwis of Formula (iii):

[1391] O O Rw3

[1392] 's' A

[1393] RW3

[1394] Rw3(in),

[1395] wherein each Rw3is independently hydrogen, halogen, optionally substituted Ci-6 alkyl, and Ci-6 haloalkyl. In certain embodiments, at least one Rw3is hydrogen. In certain embodiments, each Rw3is hydrogen.

[1396] o.,0

[1397]

[0262] In certain embodiments, Rwis:

[1398]

[1399]

[0263] In certain embodiments, Rwcomprises a benzaldehyde. In certain embodiments, Rwis a benzaldehyde. In certain embodiments, Rwis of Formula (iv):

[1400] H

[1401] (Rw5)r'

[1402]

[1403] (iv),

[1404] wherein: Rw4is hydrogen, -OH, -OCi-6 alkyl, or C1-3 alkynyl;

[1405] each instance of Rw5is halogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted Ce-io aryl, or optionally substituted 5-10 membered heteroaryl;

[1406] or any two instances of Rw5or Rw4on adjacent carbons are taken together to form optionally substituted C5-7 carbocyclyl, optionally substituted 5-7 membered heterocyclyl, optionally substituted C„.

[1407] 10 aryl, or optionally substituted 5-10 membered heteroaryl; and

[1408] r is 0, 1, 2, or 3.

[1409]

[1410] embodiments, Rwis of the formula:

[1411]

[1412] In certain embodiments, Rwis of the formula:

[1413] H

[1414]

[1415]

[0265] As described herein, L1is a bond or a linker.

[1416]

[0266] In certain embodiments, L1is a bond.

[1417]

[0267] In certain embodiments, L1is a linker selected from C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, C1-20 alkenylene, C1-20 heteroalkenylene, C1-20 alkynylene, C1-20 heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[1418]

[0268] In certain embodiments, L1comprises optionally substituted C1-20 alkylene. In certain embodiments, L1comprises optionally substituted C1-20 haloalkylene. In certain embodiments, L1comprises optionally substituted C1-20 heteroalkylene. In certain embodiments, L1comprises optionally substituted C1-20 alkenylene. In certain embodiments, L1comprises optionally substituted C1-20 heteroalkenylene. In certain embodiments, L1comprises optionally substituted C1-20 alkynylene. In certain embodiments, L1comprises optionally substituted C1-20 heteroalkynylene. In certain embodiments, L1comprises optionally substituted C3-8 carbocyclylene. In certain embodiments, L1comprises optionally substituted Cg-io arylene. In certain embodiments, L1comprises optionally substituted 3-8 membered heterocyclylene. In certain embodiments, L1comprises optionally substituted 5-10 membered heteroarylene.

[1419]

[0269] In certain embodiments, wherein -L'-Rwis of one of the following formulae:

[1420]

[1421]

[0270] As described herein, in certain embodiments, -L’-Rwis attached to an amino acid of the cyclic peptide (e.g., attached to the a-carbon, a-sidechain, or peptide nitrogen of an amino acid). In certain embodiments, -L’-Rwis attached to the a-carbon of an amino acid. In certain embodiments, -L’-Rwis attached to the a-sidechain of an amino acid. In certain embodiments, -L’-Rwis attached to the peptide nitrogen of an amino acid.

[1422]

[0271] In certain embodiments, -L’-Rwis attached to the amino acid at position 1 (i.e., -L1-Rwis attached to X1) of REF ID NO: 1. In certain embodiments, -L1-Rwis attached to the amino acid at position 2 (i.e., -L1-Rwis attached to X2) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 3 (i.e., -L1-Rwis attached to X3) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 4 (i.e., -L1-Rwis attached to X4) of REF ID NO: 1. In certain embodiments, -L1-Rwis attached to the amino acid at position 5 (i.e., -L’-Rwis attached to X5) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 6 (i.e., -L’-Rwis attached to X6) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 7 (i.e., -L’-Rwis attached to X7) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 8 (i.e., -L’-Rwis attached to X8) of REF ID NO: 1. In certain embodiments, -L1-Rwis attached to the amino acid at position 9 (i.e., -L’-Rwis attached to X9) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 10 (i.e., -L’-Rwis attached to X10) of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the amino acid at position 11 (i.e., -L’-Rwis attached to X11) of REF ID NO: 1. In certain embodiments, -L1-Rwis attached to the amino acid at position 12 (i.e., -L1-Rwis attached to X12) of REF ID NO: 1. In certain embodiments, -L1-Rwis attached to the amino acid at position 13 (i.e., -L’-Rwis attached to X13) of REF ID NO: 1.

[1423]

[0272] In certain embodiments, -L’-Rwis attached to the peptide nitrogen of an amino acid at position 9 of REF ID NO: 1. In certain embodiments, -L’-Rwis attached to the peptide nitrogen of a glycine at RW

[1424] I §

[1425] position 9 of REF ID NO: 1 to form:

[1426]

[1427]

[0273] In certain embodiments, -L’-Rwis attached to the amino acid at position 1 (i.e., -L1-Rwis attached to X1) of REF ID NO: 2. In certain embodiments, -L1-Rwis attached to the amino acid at position 2 (i.e., -L1-Rwis attached to X2) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 3 (i.e., -L1-Rwis attached to Pen*) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 4 (i.e., -L1-Rwis attached to X4) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 5 (i.e., -L1-Rwis attached to G) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 6 (i.e., -L’-Rwis attached to X6) of REF ID NO: 2. In certain embodiments, -L1-Rwis attached to the amino acid at position 7 (i.e., -L1-Rwis attached to X7) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 8 (i.e., -L1-Rwis attached to X8) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 9 (i.e., -L1-Rwis attached to X9) of REF ID NO: 2. In certain embodiments, -L1-Rwis attached to the amino acid at position 10 (i.e., -L’-Rwis attached to X10) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 11 (i.e., -L’-Rwis attached to Y) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 12 (i.e., -L’-Rwis attached to P) of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the amino acid at position 13 (i.e., -L’-Rwis attached to C*) of REF ID NO: 2.

[1428]

[0274] In certain embodiments, -L’-Rwis attached to the peptide nitrogen of an amino acid at position 9 of REF ID NO: 2. In certain embodiments, -L’-Rwis attached to the peptide nitrogen of a glycine at R™

[1429] I §

[1430] I\L A

[1431] position 9 of REF ID NO: 2 to form:

[1432]

[1433]

[0275] In certain embodiments, -L1Rwis attached to the amino acid at position 1 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 2 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 3 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 4 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 5 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 6 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 7 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 8 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 9 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 10 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 11 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 12 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the amino acid at position 13 of any one of REF ID NOs: 3-985.

[1434]

[0276] In certain embodiments, -L1Rwis attached to the peptide nitrogen of an amino acid at position 9 of any one of REF ID NOs: 3-985. In certain embodiments, -L1Rwis attached to the peptide nitrogen of a

[1435] glycine at position 9 of any one of REF ID NOs: 3-985 to form:

[1436]

[1437] Examples of Cyclic Peptides

[1438]

[0277] In certain embodiments, the cyclic peptide is selected from those in Table 2A, and pharmaceutically acceptable salts thereof. In certain embodiments, the cyclic peptide is selected from those in Table 2B, and pharmaceutically acceptable salts thereof. In certain embodiments, the cyclic peptide is selected from those in Tables 2A-2B, and pharmaceutically acceptable salts thereof.

[1439] Table 2A

[1440] Example Structure

[1441] Al

[1442] I ft I

[1443] Q J1

[1444] y X)0H

[1445] / =N V, H

[1446] HN^^NH

[1447] oX V°H°S'SV 0

[1448] HNX>'A-A

[1449] 0HHN^O

[1450] I1

[1451]

[1452] (REF ID NO: 32)

[1453]

[1454]

[1455]

[1456]

[1457]

[1458]

[1459]

[1460]

[1461]

[1462]

[1463]

[1464]

[1465]

[1466]

[1467]

[1468]

[1469]

[1470]

[1471]

[1472]

[1473]

[1474]

[1475]

[1476]

[1477]

[1478]

[1479]

[1480]

[1481]

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497] Example Structure

[1498] A90

[1499] \— - FA-OH

[1500] / o

[1501] xy V 4-9

[1502] N""70 / 0

[1503] / oA H 'll

[1504] Fy HN-~.Z'NH2

[1505] HN\ y=--OO,S H2N\su VC. t — NH NH p o J o r

[1506] \ Kiu HN-'-'X -Z7 HNA \

[1507] \— -NHJy y-NH \ NH / Q - < j7dH0A r^r cT^'N' \ J4"~N \ \^=Yu

[1508] (REF ID NO: 526)

[1509] A91 A- FA_OH

[1510] ( P yV

[1511] . V\ ry-Q

[1512] >0A M

[1513] OA ’ HN-y" NH2

[1514] J HNH, KH0“ r-'NH"... NHP °\ F p (

[1515] ! OiA N IT N A H \ A J V / F / Sr-4 P Up / ° HO"p CP"”7®HF (REF ID NO: 527)

[1516] A92

[1517] A > F5"H

[1518] A y-\ H y- / N-. A i

[1519] X-7o YH 9

[1520] / n-'AM\L

[1521] oA ' HN~A ™H2

[1522] , / A HN X ' H, N y / V^o2y-NH NH p °V-F P ( °Fy A JF FA / o Y / Y n J. F^*F HN-A0HO y x-F7H

[1523]

[1524] (REF ID NO: 528)

[1525]

[1526]

[1527] Example Structure

[1528] A97

[1529] A 0 / /

[1530] Q / \ / / ~~\ / --OH

[1531] \ JrN HN — y

[1532] N™- / / \ V-H ]

[1533] 0^= / 'Ty-0 o' \y

[1534] / =\ / ^NH 0=\ ‘M 9 0HfVo <

[1535] )MH ( s' \

[1536] 0 / \.0 0. X / y / --NH HRW H0 /

[1537] ( / y — / \ \

[1538] d v — \ —NH /

[1539] cy-s yy.9 0 HN — (REF ID NO: 533)

[1540] A98

[1541] X P f

[1542] 0 / KF-— \ / " I

[1543] y-y p| y-N \

[1544] SO J% 9

[1545] Ho / ANp-^'NH, / ~<'NSH\N0 H2N, / s2y=NH yf ^-NH ✓ NH p P (

[1546] O'X H HN-X JT N-A H \ AO V / Ju ‘ M J HN — V HO" \==J H (REF ID NO: 534)

[1547] A99 / TOx OH

[1548] / Q f \^

[1549] oK /

[1550] y-Nxpr y^ I

[1551] V7 {J,. J'H

[1552] H0^0HN-^'KNH2

[1553] HN J H N HO-J / __# / 2y=NH N H p p /

[1554] M HN--J A ’N-J H \

[1555] M / N\ 7 VNHH y-\ / 0

[1556] )r^ / / r\L7 J JN-4 HN~O ° HO-\ \^J0 H^x

[1557]

[1558] (REF ID NO: 535)

[1559]

[1560]

[1561]

[1562]

[1563] ID NO:

[1564]

[1565]

[1566] Example Structure

[1567] A112

[1568] / 0

[1569] HO y A AA

[1570] / / \ / \ zr~N

[1571] o' A o

[1572] 0 O^=\ H ij

[1573] / ==\ / HN^A-NH

[1574] / > HN d2V_# Wo w

[1575] k|H W

[1576] / O 0 W

[1577] H UMJ' ’V- / 0 -NH? HN-XJ H yJ--7 / y.NH°A ) ' A HQA / T\ — ' — \ A \=J 6 HN-y (REF ID NO: 548)

[1578] A113

[1579] \— • rvon

[1580] / p r \^J

[1581] y-NxW W

[1582] y7oow

[1583] oA^ °':L,k-NH;

[1584] 7""HA

[1585] A0<7WNHH0Yd r'-NH NH p ' P I WN w A ifmH A v— dN # Q d urs J r^r f^AwA HN-yUHO“-\ yy0 x(REF ID NO: 549)

[1586] A114 A o d y

[1587] q / A? rA_A0H

[1588] \ Ay Hte—d

[1589] N — ' ' \~~N /

[1590] oW. o' W

[1591] z=\ ) > H oy iw y

[1592] \\ / )HN- x Hkjyc.,,

[1593] \ ( / v ~ \ NH

[1594] / >JI

[1595] NH ( S \

[1596] °A \0o Yd /

[1597] pA At HNW y W P /

[1598] HrlW, Y Y^ Y^Y

[1599] / — ' — ( P / —7d HN-W

[1600] -<X / \

[1601]

[1602] (REF ID NO: 550)

[1603]

[1604] Example Structure

[1605] A117 \

[1606] 0^

[1607] ^"0 L

[1608] z A0

[1609] i 1,0

[1610] yX ©Dp

[1611] 0^NHHN.hP

[1612] Z-NH HQJ NHa

[1613] A, JI HOs / y Y \

[1614] X qiH

[1615] (REF ID NO: 553)

[1616] A118

[1617] " X)

[1618] ^"" A A H o > / ~~A

[1619] Q-^ Q A- f f~ \ / 0H

[1620] / WNHNZ

[1621] N~A / XVNZ

[1622] cWcf VJ

[1623] / ^\ ) > H O'X 1H 9 WHV <HhkJAiH \H / / \ 0==^ / \.0 O' )< C / / r^x y~NH HNW vy.o /

[1624] H\ A— NI^ / HN— ( \ N=^ 0V^~~i. )— NH / < y7M P 0’ HN~^

[1625]

[1626] (REF ID NO: 554)

[1627]

[1628]

[1629]

[1630]

[1631]

[1632] Example Structure A129

[1633] A130

[1634]

[1635] (REF ID NO: 566) Example Structure

[1636] A131

[1637] oX> °'X<^NH2

[1638] HN. •.•••" H h! / V Z < x

[1639] HO~-\ / \ „ yf ^-NH / / NHN NN p p

[1640] C

[1641] Ny "Nyj V J, < (

[1642] N'" A

[1643] y -NHHy-' HNy_ \^ p

[1644] (REF ID NO: 567)

[1645] A132

[1646] 0 / hj — < / ""i

[1647] y-N^ p| y-N \

[1648] x / y °' r x.

[1649] ■y~'s\ 9

[1650] Ho-\ RN- HY^NH2

[1651] — ZNX HN;• •-■’ H N / yJ Vr° < '2y=NH b P °V-< P C

[1652] / oX H HN-\ X N-X H \

[1653] / NH HX y4 P HC-X J d HO-'X d-)

[1654] (REF ID NO: 568)

[1655] A133

[1656] \\Qy~N / ^C^O

[1657] \ H'N~ / H

[1658] yN;

[1659] Oy O

[1660] PNH cy w 9 wHty0< CHNyNH

[1661] \ NH / v S ' |

[1662] ( g

[1663] □y \,o qHxpc /

[1664] JM V-NH HNW >-' / o

[1665] rfH \x*HM. /

[1666] 0 Hy~A / N\H /

[1667] \ / — * p —0

[1668] o' HN-^

[1669]

[1670] (REF ID NO: 569)

[1671]

[1672] Example Structure

[1673] A136

[1674] 'dw d K. o j oYHK

[1675] O-'Y HN--A w

[1676] Nu

[1677] H2

[1678] / ^\ HN H, N. d J WO / 2y^NH ^'ww \Z win " NH p °wd 9 /

[1679] HN-X rW H \Oy\J / W FW

[1680] 0HO"-\ Vw^ ° H (REF ID NO: 572)

[1681] A137

[1682] A 0 _

[1683] o. r~X / x^y

[1684] V / x>- V

[1685] KN O=<00pP 0

[1686] „ HNy'Sw2

[1687] d— \ H?N NH, '\ x * \=NH o— ( 9 \0w / i-TNV-NH HN~Y 7 J 9 r

[1688] _ j \L-d y— NH HN— \ \

[1689] dHOy ryj -yy pX\— / O’ HN-d (REF ID NO: 573)

[1690] A138

[1691] V- YV-OH

[1692] / p r \^J

[1693] 0 / \ / "'‘I

[1694] WNXqN\ J

[1695] XN"^

[1696] oY °~ HN -, 'k'NH,

[1697] / / d

[1698] O HNXH., N / X-x 9 " WNH HO- \ r-NH OY H HN~X 2? N-X H \ < N y '^y-7 / H H / "■;P HN _ 'JuHO' x^ / v X

[1699]

[1700] (REF ID NO: 574)

[1701]

[1702]

[1703]

[1704]

[1705]

[1706]

[1707]

[1708]

[1709]

[1710]

[1711]

[1712] Example Structure

[1713] A161

[1714] \ 1 Zz

[1715] oZ -'Z '

[1716] _ZZ>. Y \ HN- X / Z \ J f J 7 1

[1717] V HN'o. Aff\ yk / S) (X^ZV^

[1718] oXHHNJHP

[1719] X 7 SIH, Htl ZZ~ «H Hn'2

[1720] O' \ X / \

[1721] no Z 'ldHkZ Y ‘ XO T Z' IZ '111L KANH \ H

[1722] n HN^

[1723] (REF ID NO: 597)

[1724] A162

[1725] Ck NHn AHY-NIA

[1726] Yx uo YY

[1727] %. J H \

[1728] Y S

[1729] 0i 0 °

[1730] (X J A N I il Y 9 Y 'trW

[1731] L If I ’ H l

[1732] J n HX 1 Y^NH / 0HCT ^ j

[1733]

[1734] (REF ID NO: 598) Example Structure A163

[1735] A164

[1736]

[1737] (REF ID NO: 600)

[1738]

[1739]

[1740]

[1741]

[1742]

[1743]

[1744]

[1745]

[1746] Example Structure A181

[1747] A182

[1748]

[1749] (REF ID NO: 618)

[1750]

[1751]

[1752]

[1753] Example Structure A189

[1754] (REF ID NO: 625) A190

[1755]

[1756] (REF ID NO: 626)

[1757]

[1758]

[1759]

[1760]

[1761]

[1762]

[1763]

[1764]

[1765] Example Structure A207

[1766] (REF ID NO: 643) A208

[1767]

[1768] (REF ID NO: 644)

[1769]

[1770]

[1771]

[1772]

[1773]

[1774]

[1775]

[1776]

[1777]

[1778] Example Structure A227

[1779] A228

[1780]

[1781] (REF ID NO: 664)

[1782]

[1783]

[1784]

[1785]

[1786]

[1787]

[1788]

[1789]

[1790]

[1791]

[1792]

[1793]

[1794]

[1795]

[1796]

[1797]

[1798]

[1799]

[1800]

[1801] Structure A267

[1802] A268

[1803]

[1804] (REF ID NO: 704)

[1805]

[1806]

[1807]

[1808]

[1809]

[1810]

[1811]

[1812]

[1813]

[1814]

[1815]

[1816]

[1817]

[1818]

[1819]

[1820]

[1821]

[1822]

[1823]

[1824]

[1825] Example Structure

[1826] A309

[1827] A310

[1828]

[1829] Cyclic Peptide Dimers

[1830]

[0278] Also provided herein are conjugates (“dimers” herein) comprising two cyclic peptides described herein, wherein the two cyclic peptides are conjugated to one another via a bond or a linker.

[1831]

[0279] In certain embodiments, for at least one of the cyclic peptides, the linker is attached at:

[1832] X1ofREF ID NO: 1;

[1833] X2of REF ID NO: 1, wherein X1of REF ID NO: 1 is absent; X3of REF ID NO: 1, wherein X1and X2of REF ID NO: 1 are absent;

[1834] X1of REF ID NO: 2;

[1835] X2of REF ID NO: 2, wherein X1of REF ID NO: 2 is absent; or

[1836] Pen* of REF ID NO: 2, wherein X1and X2of REF ID NO: 2 are absent.

[1837]

[0280] the two cyclic peptides are conjugated to each other via the N-terminus of each cyclic peptide.

[1838]

[0281] In certain embodiments, the linker comprises alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, 5 heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[1839]

[0282] In certain embodiments, the linker comprises a bond, C O alkylene, C O haloalkylene, C O heteroalkylene, CMO alkenylene, CMO heteroalkenylene, C O alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Ce-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[1840]

[0283] In certain embodiments, the linker is a bond, alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, 5 heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[1841]

[0284] In certain embodiments, the linker is a bond, CMO alkylene, CMO haloalkylene, CMO heteroalkylene, CMO alkenylene, CMO heteroalkenylene, CMO alkynylene, CMO heteroalkynylene, C3-8 carbocyclylene, Cg-io arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

[1842]

[0285] In certain embodiments, a dimer described herein comprises a lipid group, and the lipid group is attached to the linker conjugating the two cyclic peptides. In certain embodiments, the linker is or comprises:

[1843] H N

[1844] Nn2N OH

[1845] H n H

[1846] o

[1847]

[1848] , wherein n2 and pl are as described herein. In certain embodiments, the linker is or comprises:

[1849]

[1850] described herein.

[1851]

[0286] In certain embodiments, the linker is selected from

[1852]

[1853]

[1854]

[1855] O

[1856]

[1857]

[1858] embodiments, the linker is selected from

[1859]

[1860]

[1861] 

[1862]

[1863]

[1864]

[0288] In certain embodiments, neither, one, or both of the cyclic peptides of the dimer may comprise a group of the formula: -L’-Rw. In certain embodiments, neither of the cyclic peptides of the dimer comprises a group of the formula: -L’-Rw. In certain embodiments, exactly one cyclic peptide of the dimer comprises a group of the formula: -L’-Rw. In certain embodiments, both cyclic peptides of the dimer independently comprise a group of the formula: -L’-Rw.

[1865] Examples of Cyclic Peptide Dimers

[1866]

[0289] In certain embodiments, the cyclic peptide dimer is selected from those in Table 2B, and pharmaceutically acceptable salts thereof.

[1867] Table 2B

[1868] Example Structure

[1869] Bl / ^ / OH

[1870] Ju

[1871] U 1 N H'V n Y 1J Vo H

[1872] 0Q^N / H2N N

[1873] AH> NH J ^> 0 OH J1', 1 U X J >“NH2AsY fl °YS TA H fl l H V r-C r\ O ^ILHNR° OHV^'VH UN,'AJNVHNrY T JAAHH° J °HA %< V

[1874] / NJ oHHUNH2H%OHXX H <" Nj^T O X^ NH,, O AZ" / 1X X-MAY^ X o \ X o N Y YA A U

[1875] (REF ID NO: 62)

[1876] B2 x^ / OH

[1877] JU

[1878] T H n I Vo H

[1879] oVT 0 A / H2N N

[1880] AH> NH J 0 OH j1', r H X J J-NH2x01SU fl ° i ’ AHH V -A O r ll IOvjHnU 1 ''N 1X1X TJHY A LIV / / YVHNYU 1 Y L X^iXlNHU / I\-' JNIMH HL VX 0 I JHO X 0 XHU° ° 1 O^T Y^ N A^O M HN i^ l lHNA [ZNX OHHNXH2H%OHV-. H <'NJ^ O X^ NH,, O r A O 1

[1881] X II

[1882] o'Y: N H

[1883] X N Y K IXY o1Y1

[1884] I T

[1885] ^NH U

[1886]

[1887] (REF ID NO: 63)

[1888]

[1889]

[1890] Example Structure

[1891] B9 O l

[1892] 2 A

[1893] VHN^1^NH f Y^° oAyU Y O Y o °YNH / -N °YN H°YU?

[1894] H\AUNHHN NH2CK. NHHO

[1895] o^ s'^ ^o HJ OH

[1896] HN. A U— A. X\ -A A Y N?r \ I HN^O °H H*Y° oH0A °HY ° °YS A\NY^NV / NV S HN Yj A 1HJ!HO UXAM YJ L j T Y j) ANHST AA AA o OH (REF ID NO: 70)

[1897] BIO x^, OH

[1898] JU

[1899] O^NH2

[1900] cyxHoOYN-J

[1901] UHrs° U?HA A JH2A Ihi A* v jsA CJ ^HNY° O V‘" N A YA '-AYNyVHNyV Y YjLJx A *NHjX OHO L NHO xL O

[1902] HN Y [* || Y|^NH2 HN^O

[1903] “’S'V0' ^' f0 HNY° N_J 0 OH NH

[1904] HNO^NHu0 r^' o x\

[1905] |'-S-NYAN^fN- A.0\xA. °

[1906] N Y II ^1 ^NH U

[1907] (REF ID NO: 71)

[1908] Bll Xx^x'OH

[1909] AJ AS^N^ Y- %~NH2

[1910] °yN^Ho0YNY

[1911] Y A i n °K A A Y i A SHS J H y f lNr\ A YYHNY° O Y Y Y Y YNVY VHNYV Y UU- AJNHJU OHo UHo X o A -"'1oYY AHU1YY°HNY°< ZNU ° °H<NH

[1912] HNCr 'NHu0 Uo X-J rW rX A. o o

[1913] N A A n AH M

[1914]

[1915] (REF ID NO: 72) Example Structure

[1916] B12

[1917] °'VNH2

[1918] H0OANA

[1919] °yVHrsO o on, NH Y s. / i_i MJL YY X\Z~NH2Y f0i r u H i o H § [ H v f i n O AA Jx YXJ 0H0 LUNH ° A 0 Ax < W AHU o Yr0 HNY° N^ A 0 OH. NH x J-.. <" j r f "" IHNO^NH 0 Y'o Yx YArY

[1920] NV W A A U < (REF ID NO: 73)

[1921] B13. X. OH

[1922] Ju

[1923] <YNH2

[1924] OyNY OOYNY

[1925] °YMHrsI A?H / NHY s. / Y Y. J1 / \ YH2Y r01 r u H ] uHu M V J ’ o O YW o V> VNYJ-''N A -N' / tVNYsJ HNYN;T kxJx-J'' JY. NH YxJ 0HO LY O X 0 Ax ••"' oAV AHV1A °HNY°< ZA ° °HrNHA--.,,HNO^NHu0 A

[1926] NV W ° V ^NH U < (REF ID NO: 74)

[1927] B14

[1928] 1 H 1 "

[1929] °YN-AAyO

[1930] V J1 H NVY1 ^nhV

[1931] V^° O^NVOH NV 0 / V0

[1932] / -N °YNH°V VN Y AHNVXANHH\ / N H2°YNH H 0

[1933] Y°H° S'S-V HJ QH / NVHNy 'NUJV o cr^V^ HN' XI ° VHV °h° VH2°HV ° °YS W ANW '■• W s HNAY A HAJ 2H2 M A

[1934] T | „ jrNH2 Y O M o iH

[1935]

[1936] (REF ID NO: 75) Example Structure

[1937] B15

[1938] n 1 "

[1939] -cAArP1 H, / Y |lRNH

[1940] 0H NP o f n o

[1941] / =N OyNH < AArN^VHN\AAxkll lHN?NH2 O^NHH0 k^O ''VX' jNH>••■< Y T I crx| V° O S'S 0HI\T OH

[1942] HN^ J-., JL Jr— >x Y Y 'NX\ I HN^O °H HA°O Ho A oHv O °Y\ A ANY^NANAN'A'S HN A% A 1HA A A IAAM A il □ 1 Y j) ^N H2 T AA o OH (REF ID NO: 76) B16

[1943] y

[1944] \ °j AN A HN— ( > H2N Q y— ' y,— CA0^YNA° Y

[1945] N— 'XAN )=NH < HN— <

[1946] A VNH

[1947] 4 HN^. AO' — (

[1948] \ A-( )=0A JNH 0\0H°\ r~z

[1949] ANH S HNA Z=\

[1950] _N ANH HNA HNA

[1951] — K ANH HN—% AN. — < OQNV < 5 r- /

[1952] o < ANH ON — /

[1953] A ANH; AH

[1954] \ / HNo u — \0H0\ / —

[1955] A} ANH

[1956] HN— /

[1957] (REF ID NO: 77)

[1958] B17 HO

[1959] OVNH20M

[1960] 4LO / — YA°HAA Y'H^”” A( zp \ o A / ^= / O u,s H 0 0 HNY )— HN— < H2N y—s

[1961] X\-N J )=NH < HN"-( — N

[1962] 0=( 0 HN o4V— Z )=o )=0 z=\ ) 0 =( ^ V- O HN / ( ^ HN HN>..-'^O' — < 3 — (N—

[1963] ^— \ )=OJNH 0=\ °H°K / —

[1964] N— ( 0=( HN^. V— NH O

[1965] s' ) A— NH HN— Z / =\

[1966] A X A / P0A A )

[1967] ^N y— NH — C / — '■ O 0 HN— Z HN— Z < Ov—JuJT A* )r\ / -"NH H'N\ A(0Y A

[1968] HN^ / Q / HNY NH ' — y Y" NH < JJ

[1969] 0 Z ^NH HO— \ N

[1970] YNH20 0' \

[1971] e 2 HN ' - <

[1972]

[1973] (REF ID NO: 78)

[1974]

[1975] Example Structure

[1976] B21

[1977] HO— —,, /

[1978] \ / / P

[1979] ) — -"-X / — NH N— \ /

[1980] v _ / \= / o C ° C°

[1981] \ MHN“( 7\ J >° < / =\ Mx>^N J H2N'K<-NH NH <\ / >

[1982] 0°=c °5- /

[1983] 4 J HN S HN

[1984] \ )=0J X / ° °\ )

[1985] p O ) — \ V— NH HN— (=O

[1986] N- NH s' VNH HN-< '-A'IL.

[1987] O=( OHO PC / — ' ✓ — o \^NHy— NH — ( / — (, — ' HO

[1988] u HFN-VQ / HN— / ’"NH0

[1989] 0

[1990] (REF ID NO: 82)

[1991] B22 HO

[1992] F ° rCr o^NH2rH

[1993] j — i / "NV-\ ° V\ N )rNP CB^° HA-'

[1994] 0 J H2N I S _ /

[1995] TsY°

[1996] V

[1997] W >° / / VH U M

[1998] NH OHQM- C J..,NHCNC\0=Z H _-Z 7 X|_Z 'OH \ HHN-< \NC / NM J'"NHo

[1999] 0H 0 \—N

[2000] o N

[2001] H

[2002] (REF ID NO: 83)

[2003] B23

[2004] ) —

[2005] 9\ C / ° o NC^N / '

[2006] o^z \ HN-~X ka / ~'OH / I, — \ k. -C-'

[2007] N^ / ^N JO O > rik-X,NH>" Uo ' X Z Y pNH ° L ° \ NH2< < ° ' HNV,4 s ' z^--, O^Z / 0 \ S O== / \\,\ / =NV '3zx \ 7^ MH° V K M° % HN?'■"

[2008] HN„. ANH N_X0HNY H HN^ / ;.„OHS •N<)

[2009] NH

[2010]

[2011] (REF ID NO: 84) Example Structure

[2012] B24

[2013] 1 ft

[2014] TH? V I L 1 Y

[2015] Sr0Y° °^\-"\0H Ny o AH FT / =N \ S / ^NXS[XN'^XN / HN\A\^AkNllHl\ HN NH2O^NHHo M \ \._, / y y Q^S | 0 S'S 0 HNcY HTT ^^ xNx / xJA'lHY" NM ohn^°0 H HV °H° rh°HV° ° °YS A\NrUlNArN„ ANYS.SHNM A 1hUHo L £AM, O [ l l [ 1 MNH2

[2016] MH0OH HN^NH2

[2017] (REF ID NO: 85)

[2018] B25

[2019] 1 ft

[2020] IHli V \ L 1 Y

[2021] T ^° HZ °OY"\0H NA 0 Af ft

[2022] / -N VHJ VNYHN\AX^AK11 1< HN NH2O^, NHHO M IH) >••"< Y y O^Y | 0 S"S 0HN^

[2023] HN^ J-,zJL A — x^ v xk^ y N \ 0 0 HN^O ° AHY°0H0ANHYy° ° °Y\ UA VYW '' A'- SY HN A H2NHJ n °H 5U i SlAY Z^NH2Y O M OzIH (REF ID NO: 86)

[2024] B26

[2025] 1 H

[2026] OyNYN-^°

[2027] HN^ / \x?\

[2028] 1H,i \ \ Ml ^“N\HY

[2029] nY HN^ ° NY^OH M FT FT

[2030] / -N °yNH) °Y ^ AN YNHN\A\xzAk ll l\ HN NH2O^, NHHO L XO

[2031] NjH) >■•"< Y A

[2032] \ O SxS° HN^ N.^ / 'YS

[2033] HN. JL A — U A.

[2034] Y II 'N LI - \ - o HN 1 ^O O HN^ xO ~ JHN^xO ~ O^x<

[2035] 1 °H° \ ° 1 1 SNZ^X / VN',-rAN'''SrS's HNAyN\

[2036] 1ho L XAM Y r j [ 1 [ 1 MNH2 T Y / o OH

[2037]

[2038] (REF ID NO: 87)

[2039]

[2040] Example Structure

[2041] B30

[2042] JYJ HO

[2043] Q °-VNH2

[2044] °VN? G0 HXS1nH ft 1 r Z J \ k / H2NP 2N* |f V0°^ ' O HNST O H \ \ H 0 LHJA^O 0 HN^Z 1 P J VY K 0 pNH?HN1 X... J oPoH VU 0 & NA / > YYNY ANHP\fh\ P° P zP AHJX

[2045] > C / Y Y H fYY y < j NS ° JO

[2046] N H ^NH O

[2047] (REF ID NO: 91)

[2048] B31

[2049] n i?

[2050] P HN^A ^

[2051] pXo0 / P HOVZ

[2052] _ CK. N 1 H ° 0 X HN 1. Z V\ V '—YP' -. o \\ N— / fO / ^N 1 7 T / / ) r-A ■• Z ~~f \ / HN\PP HN X ) p

[2053] QP| \ °yP / =o° P0°NHZPHNV>o <NHoH\ °P., / A % rV -Y -P " P

[2054] • < X " X X

[2055] X P \ 0 H P \Nvp^ \ \ l^vNX H / NH

[2056] II H 0 / / O

[2057] O OCx^=

[2058] (REF ID NO: 92)

[2059] B32

[2060] 1 H A

[2061] HN”J lHN'YZP<P1N”P [fP

[2062] L T J XP H J JI J

[2063] yX) O^NYOHY 0 ( H0

[2064] , N. O^, NH O^X-P XP.. P / N, AKI / (l J IT N fl N LAPNHUN NH2o NHH0 U° Y Y X HX V HN^ J-,, JL A— J\ Js. Y N T \ 0 O-^Y HN^O o J! HN. ~ JANHJHN^O 0< Xs^ A Y U H 9 f HNY Y 9 Y > VPPPrNx^NP'N'-A''Vs HNM A H2NHJ sHI UYAM. P Q n | | XNH2 T 0 M OzJH

[2065]

[2066] (REF ID NO: 93) Example Structure _ (REF ID NO: 94) B34

[2067] (REF ID NO: 95)

[2068]

[2069] (REF ID NO: 96)

[2070]

[2071]

[2072]

[2073]

[2074]

[2075] Example Structure

[2076] B46

[2077] A * r / V1

[2078] rUry' '5-CJ

[2079] yS >” Xr

[2080] \ » j -M.. M

[2081] t~r *

[2082] . P XX?,< ' W " \ / ■ "■" y > HP *., s. C XX) Z « > >, '*O V=o FW'

[2083] / ^\...~ / z / V ' )HOAZ

[2084] (REF ID NO: 121O M

[2085] B47, C!j-i

[2086] £5

[2087] *'“xzZS

[2088] V A-x-'^V VH< <s OH

[2089] s. P? ~

[2090] cZ i

[2091] zxizl::v n v- x yP'

[2092] XxrMXj W A cxy...5flXZ'sXo 'O0c V V rev,p0

[2093] ,!rVyk »o-Cj

[2094] (REF ID NO: 167)

[2095] B48. ON

[2096] 'X

[2097] X xxr6Xo?' ’ '’XCu >rX. y

[2098]

[2099] (REF ID NO: 168)

[2100]

[2101]

[2102]

[2103]

[2104] Example Structure

[2105] B56

[2106] *

[2107] (REF ID NO: 176)

[2108] B57

[2109] .^..i ' ‘”|b?■ H >“•■: ' \s<:

[2110]

[2111] (REF ID NO: 177)

[2112]

[2113] Example Structure

[2114] B60

[2115] 'A;.. i

[2116] oy A F h

[2117] rtSUr •; >x'

[2118] . A

[2119] rAb A,,:y Av zX -<i / P

[2120] (REF ID NO: 180)

[2121] B61

[2122] yx J ^o i

[2123] .-. U H Af AH >~m.

[2124] «0r5 ‘ y- o A" XA v <?.< C,.... XX JXA " AI X^ ocx oA yr^ xw ‘ X o^co UcrO ry ~uX ° y y v. X? -y Gi z- ' M. N~« H... X 2 X H A 7 A£. '^'C;' 'OH>--J1 6 H i-kH -XxX

[2125] „XJ

[2126] (REF ID NO: 181)

[2127] B62

[2128] H xc

[2129] y f r"\

[2130] 4£yoA*' / °P " X cirt^K <y A. v o,s, y.. Aj Ayo.yxo, » ifv oO-'v^-y

[2131] 1r'"1A.0 -K X / ’ X-.y-A x-X,...

[2132] V- H V... r - -i, H j \ 'v■?:. / ■'■r Y':''Yy

[2133] J-> A

[2134] J

[2135]

[2136] (REF ID NO: 182)

[2137]

[2138]

[2139]

[2140]

[2141]

[2142]

[2143]

[2144]

[2145]

[2146]

[2147]

[2148]

[2149]

[2150]

[2151]

[2152]

[2153]

[2154]

[2155]

[2156]

[2157]

[2158]

[2159]

[2160]

[2161]

[2162]

[2163] ID NO:

[2164]

[2165]

[2166]

[2167]

[2168]

[2169]

[2170]

[2171]

[2172] Example Structure

[2173] B129

[2174] <■'* / A „ Z” > 'V - ■ s QW’1' ( 0 rl >w iiAq V )

[2175] O'

[2176] \ □

[2177] Zk K

[2178] uXssO

[2179] „XhlHHf., Zrf!w w -£r r < Z / 1 HN 3o > 'NH \ r*» / A, JZ0HiV NH w / ‘" WH V / / ■’■ft V z iL / / z

[2180] 0H"‘ V

[2181] (REF ID NO: 776)

[2182] B130

[2183] <-CHH

[2184] Hv. w M X

[2185] / -yZ x yO

[2186] Q> 3 ^’

[2187] MH s <- K'"

[2188] ' y-<2Zrf <e- ><;0 04

[2189] CLNH { A ■;'->, SH / \= / 13 3^ xh-3

[2190] HO~4 $C’ )

[2191]

[2192] (REF ID NO: 777)

[2193]

[2194]

[2195] Example B134

[2196] B135

[2197]

[2198]

[2199]

[2200]

[2201]

[2202]

[2203]

[2204]

[2205]

[2206]

[2207]

[2208]

[2209]

[2210]

[2211] Example Structure

[2212] B162

[2213] G

[2214] 'XC. FT0An

[2215] ■J,. ■. Y ”..<» F / K / NH* C n kHff 1 r. ' H / HT KVO x fX0V b '6 X J H

[2216] A o 5v> \r ° AHHOAJ

[2217] (REF ID NO: 809)

[2218] B163 1 H

[2219] xx-4k^7

[2220] AxAX' y- S a ASXky ■""«■ k — 7'iH;zS ) vHpt~ — k 7'^(A° Y"? « * F t r H f -V / ~~^0A'

[2221] . - OrXT'HU UH py A G6 0M

[2222] (REF ID NO: 810)

[2223] B164

[2224] (>= / L.,y \J G r h b <fL~\ q_A<!kL« ' \, »r G vk k F \

[2225] C k-7X / XH H'---# < V < ti-J o v z— )— -MH > y J < J-J0YY, X S

[2226] \ >-NH}Y'\\ r AY,_' XrXr3 7 / AH WH HN'L l

[2227] -^Y A;0° \ HA? ’

[2228] «,»vy

[2229] A kA

[2230] y-Y / p>.

[2231] !'ri

[2232]

[2233] (REF ID NO: 811)

[2234]

[2235]

[2236]

[2237]

[2238]

[2239]

[2240]

[2241]

[2242]

[2243]

[2244] Example Structure

[2245] B184

[2246] Y H 11

[2247] u Xrt0jO

[2248] oJ^ X« p

[2249] / SlHH< j NH,

[2250] 1 AV 2 t

[2251] O HO

[2252] €_ V— z f

[2253] 0 / ^ Jl s — (f Jj

[2254] A” H I......

[2255] VYYL JQ G Q^^'-F 1

[2256] “ 0 > H > TH ■■«• X / „

[2257] z".

[2258] ... _ J4H JF^,

[2259] t I L wz

[2260] 0<s^Y I 1

[2261] j o

[2262] (REF ID NO: 831)

[2263] B185 jy.°H

[2264] H p

[2265] %[TV vQq

[2266] V fi' J] 1 -.OG " "it’<H— i ^-NH2

[2267] oA / A

[2268] ? HN^P / J \_-.

[2269] . X&^AC X ' rO '^LP A Yz,:Ar CD r>» A"' d A

[2270]

[2271] (REF ID NO: 832)

[2272]

[2273]

[2274]

[2275]

[2276]

[2277]

[2278]

[2279]

[2280]

[2281]

[2282]

[2283]

[2284]

[2285]

[2286]

[2287]

[2288]

[2289]

[2290]

[2291]

[2292]

[2293]

[2294]

[2295]

[2296]

[2297]

[2298]

[2299]

[2300] Example Structure

[2301] B238 0

[2302] <- -J - 7 M > < ) < H r - A '1 - 7 0 X“ F H t ’ F 'X a 1 f H F “¥ ' ’ C — K A T" ox < / ^yV WvV'-'X €( ° °

[2303] (REF ID NO: 885)

[2304] B239

[2305] <3. H (J CH

[2306] y / / r / / HXN—\ / z 's^=. /

[2307] \~ / T ' #'"r'O

[2308] t

[2309] Q< S X'SHI

[2310] .. T V yj<n

[2311] Q;':5° "^X ( X-Z A J' rX. Z X \ X * As<. o o \ X HN r "^,.. CHX

[2312] '1A-AS. S- O<NH''\yV (REF ID NO: 886)di4

[2313] B240

[2314] 'JL Jj "x > JM^XFA-W v-X^-cO Aox f pFr\xv O XCXcx <r f V AXoJI C « M-X

[2315] < J? Xu XXX < 7 ° * > X-,rW0< p1 \x>

[2316]

[2317] (REF ID NO: 887) i-iO

[2318]

[2319]

[2320]

[2321]

[2322] Example Structure

[2323] B249 H p

[2324] o, l r~~\ /

[2325] . W-N HN— <

[2326] qi0<

[2327] > \ P O.z< M

[2328] fU HN-yNHHO^

[2329] / ° C^ML Q

[2330] O ^sssZ 0 rr ' —j \3 / ) P 1 S ■: C < UM_7\ X AJ x x °u\ y H^C > r b

[2331] w

[2332] pio~-4 y~~ / *■*V

[2333] (REF ID NO: 896)

[2334] B250 A 11

[2335] xhr s jXf HtT '■’ w Xj]<ifi

[2336] XXL>AXP» v.. X drX C.

[2337] / - J -y ZT: p" fr „

[2338] X Zx Y M°>? r H V W A

[2339] oX X ‘r'". X X ° tx,6° -X

[2340] (REF ID NO: 897)

[2341] B251 OB

[2342] X X 4'X X

[2343] \LH / L \.:v

[2344] X V xXM •« <

[2345] <>. / (< WX

[2346] vX C x X '"

[2347] ■ x X

[2348]

[2349] (REF ID NO: 898)

[2350]

[2351]

[2352]

[2353]

[2354]

[2355]

[2356]

[2357]

[2358]

[2359]

[2360]

[2361]

[2362]

[2363]

[2364]

[2365] (REF ID NO: 929)

[2366]

[2367] (REF ID NO: 931)

[2368]

[2369]

[2370]

[2371]

[2372]

[2373]

[2374]

[2375] (REF ID NO: 945)

[2376]

[2377]

[2378]

[2379]

[2380]

[2381]

[2382]

[2383]

[2384]

[2385]

[2386]

[2387]

[2388]

[2389]

[2390]

[2391]

[2392]

[2393]

[2394]

[2395]

[2396]

[2397] Physical Property Modifying Groups

[2398]

[0290] A cyclic peptide or dimer described herein can further comprising one or more physical property modifying groups. Examples of physical property modifying groups include, but are not limited to, basic amines (e.g., morpholine), quaternary amines, PEGlylation, glycosylation (e.g., sugars), carboxylic acids and acid isosteres (e.g., tetrazole, oxazolidinone), sulfonic acids, phosphonic acids. A physical property modifying group may be incorporated at any position of a cyclic peptide or dimer described herein, such as at any amino acid, crosslink, linker, or lipid group.

[2399] Additional Embodiments

[2400]

[0291] Additional embodiments are indicated by the following numbered paragraphs:

[2401] 1. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:

[2402] X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(REF ID NO: 1), wherein:

[2403] X1is aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement; X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;

[2404] X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via an X3-X13crosslink;

[2405] X4and X10are crosslinked amino acids connected via an X4-X10crosslink;

[2406] X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or is absent;

[2407] X6is a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;

[2408] X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;

[2409] X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);

[2410] X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile); and

[2411] X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; and

[2412] X12is proline (P), D-proline (D-Pro), or a proline replacement.

[2413] 2. The cyclic peptide of paragraph 1, or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide comprises the amino acid sequence:

[2414] X1-X2-Pen*-X4-G-X6-X7-X8-X9-X10-Y-P-C* (REF ID NO: 2), wherein Pen is penicillamine and * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink.

[2415] 3. The cyclic peptide of paragraph 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1is a lysine replacement.

[2416] 4. The cyclic peptide of any one of paragraphs 1-3, or a pharmaceutically acceptable salt thereof,

[2417] RN

[2418] wherein X1is a lysine replacement of Formula (h

[2419]

[2420] -2): O (h-2), or a D-isomer thereof, wherein:

[2421] m is 1, 2, 3, or 4;

[2422] each R1is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;

[2423] R3is hydrogen or Ci-6 alkyl; each instance of RNis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -C(=0)RB, -S(=O)2RB, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RNattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; and

[2424] each RBis independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

[2425] 5. The cyclic peptide of any one of paragraphs 1-4, or a pharmaceutically acceptable salt thereof, wherein X2is phenylalanine (F).

[2426] 6. The cyclic peptide of any one of paragraphs 1-5, or a pharmaceutically acceptable salt thereof, wherein X4is glutamic acid (E), lysine (K), or a lysine replacement; X10is N-methyl-glutamic acid (NMeE) or is N-methyl-lysine (NMeK); and X4and X10are crosslinked to form

[2427]

[2428] O or O wherein each a represents the point of attachment to the a-carbon of X4or X10

[2429] 7. The cyclic peptide of any one of paragraphs 1-6, or a pharmaceutically acceptable salt thereof, wherein X6is a histidine replacement.

[2430] 8. The cyclic peptide of any one of paragraphs 1-7, or a pharmaceutically acceptable salt thereof, wherein X7is phenylalanine.

[2431] 9. The cyclic peptide of any one of paragraphs 1-8, or a pharmaceutically acceptable salt thereof, wherein X8is glycine (G).

[2432] 10. The cyclic peptide of any one of paragraphs 1-9, or a pharmaceutically acceptable salt thereof, wherein X9is a sarcosine replacement.

[2433] 11. The cyclic peptide of any one of paragraphs 1 - 10, or a pharmaceutically acceptable salt thereof, wherein the C-terminus of the cyclic peptide is amidated (-NH2).

[2434] 12. A dimer, or a pharmaceutically acceptable salt thereof, comprising two cyclic peptides, wherein:

[2435] the two cyclic peptides are independently cyclic peptides of any one of paragraphs 1-11; and the two cyclic peptides are conjugated to each other via a bond or a linker.

[2436] 13. The dimer of paragraph 12, wherein the two cyclic peptides are the same.

[2437] 14. The dimer of paragraphs 12 or 13, wherein the two cyclic peptides are conjugated to each other via the N-terminus of each cyclic peptide.

[2438] 15. The dimer of any one of paragraphs 12-14, or a pharmaceutically acceptable salt thereof, wherein the linker comprises C O alkylene.

[2439] 16. The cyclic peptide or dimer of any one of paragraphs 1-15, or a pharmaceutically acceptable salt thereof, wherein the dimer further comprises a lipid group.

[2440] 17. The cyclic peptide or dimer of any one of paragraphs 1-16, or a pharmaceutically acceptable salt thereof, wherein the lipid group comprises one or more of the following in any combination: , wherein nl is 1, 2, 3, or 4;

[2441] o o

[2442]

[2443] , wherein pl is an integer from 1-30, inclusive.

[2444] 18. The cyclic peptide or dimer of any one of paragraphs 1-17, or a pharmaceutically acceptable salt thereof, wherein the lipid group comprises:

[2445]

[2446] wherein n2 is 0, 1, 2, 3, or 4.

[2447] 19. The dimer of any one of paragraphs 12-18, or a pharmaceutically acceptable salt thereof, wherein the lipid group is attached to the linker conjugating the two cyclic peptides.

[2448] 20. The dimer of any one of paragraphs 12-19, or a pharmaceutically acceptable salt thereof, wherein the linker comprises:

[2449] O

[2450]

[2451] Pharmaceutical Compositions, Kits, and Administration

[2452]

[0292] The present disclosure provides pharmaceutical compositions comprising a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, a cyclic peptide or dimer described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[2453]

[0293] The terms “composition” and “formulation” are used interchangeably herein.

[2454]

[0294] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the cyclic peptide or dimer described herein ( / .<?.. the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi -dose unit.

[0295] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[2455]

[0296] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[2456]

[0297] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition. Examples of excipients which adapt a composition to a desired route of administration are, for example, but not limited to, for oral administration, absorption enhancers promoting absorption from the gastrointestinal tract, for transdermal or transmucosal administration, penetration enhancers, for example, those employed in adhesive skin “patch” or compositions for buccal administration.

[2457]

[0298] An “absorption enhancer” is a component that improves or facilitates the mucosal absorption of a drug in the gastrointestinal tract, such as a permeation enhancer or intestinal permeation enhancer. As conventionally understood in the art, “permeation enhancers” (PEs) are agents aimed to improve oral delivery of therapeutic drugs with poor bioavailability. PEs are capable of increasing the parace llular and / or transcellular passage of drugs. Pharmaceutical excipients that can increase permeation have been termed “absorption modifying excipients” (AMEs). AMEs may be used in oral compositions, for example, as wetting agents (sodium dodecyl sulfate), antioxidants (e.g. EDTA), and emulsifiers (e.g. macrogol glycerides), and may be specifically included in compositions as PEs to improve bioavailability. PEs can be categorized as to how they alter barrier integrity via paracellular or transcellular routes. “Intestinal permeation enhancer (IPE)” refers to a component that improves the bioavailability of a component. Suitable representative IPEs for use with cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, include, but are not limited to, various surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitine and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, and chitosans, other mucoadhesive polymers and the like.

[2458]

[0299] In some embodiments, cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided to a subject in combination with permeation enhancers that promote the transport of the peptides across the intestinal mucosa by increasing paracellular or transcellular permeation. For example, in one embodiment, a permeation enhancer is combined with a cyclic peptide or dimer described herein, wherein the permeation enhancer comprises at least one of a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In one embodiment, a permeation enhancer comprising sodium N-[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalent association with the cyclic peptide or dimer described herein, wherein the permeation enhancer favors membrane transport and further dissociation once reaching the blood circulation. In another embodiment, a cyclic peptide or dimer described herein is conjugated to oligoarginine, thereby increasing cellular penetration of the peptide into various cell types. Further, in at least one embodiment a noncovalent bond is provided between a cyclic peptide or dimer described herein and a permeation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancer reduces peptide aggregation and increasing stability and solubility for the cyclic peptide or dimer described herein.

[2459]

[0300] The absorption enhancer may be, e.g., a zwitter-ionic absorption enhancer, a cationic absorption enhancer, an anionic absorption enhancer (e.g., an anionic absorption enhancer comprising one or more sulfonic acid groups (-SO3H)), or a non-ionic absorption enhancer, particularly a zwitter-ionic absorption enhancer or a non-ionic absorption enhancer. It is preferred that the absorption enhancer is selected from Cs.2o alkanoyl carnitine (preferably lauroyl carnitine, myristoyl carnitine or palmitoyl carnitine; e.g., lauroyl carnitine chloride, myristoyl carnitine chloride or palmitoyl carnitine chloride), salicylic acid (preferably a salicylate, e.g., sodium salicylate), a salicylic acid derivative (such as, e.g., 3-methoxysalicylic acid, 5 -methoxy salicylic acid, or homovanillic acid, a Cs-2o alkanoic acid (preferably a Cs-2o alkanoate, more preferably a caprate, a caprylate, a myristate, a palmitate, or a stearate, such as, e.g., sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate), citric acid (preferably a citrate, e.g, sodium citrate), tartaric acid (preferably a tartrate), a fatty acid acylated amino acid (e.g., any of the fatty acid acylated amino acids described in US 2014 / 0056953 Al which is incorporated herein by reference, including, without being limited thereto, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L- aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-giutamic acid, sodium lauroyl glutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L- histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methioninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl proiinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L- tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, sodium capric cysteinate, N-decanoyl- L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric giutaminate, N-decanoyl-L-glutamine, sodium capric glycinate, N-decanoyl-L-glycine, sodium capric histidinate, N-decanoyl-L-histidine, sodium capric isoleucinate, N-decanoyl-L-isoleucine, sodium capric leucinate, N-decanoyl-L-leucine, sodium capric methioninate, N-decanoyl-L- methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric proiinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decylleucine, sodium stearoyl glutamate (e.g., Amisoft HS-1 1 P), sodium myristoyl glutamate (e.g., Amisoft MS-1 1 ), sodium lauroyl glutamate (e.g., Amisoft LS-1 1 ), sodium cocoyl glutamate (e.g., Amisoft CS-1 1 ), sodium cocoyl glycinate (e.g., Ami lite GCS-1 1 ), sodium N-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, sodium lauroyl alaninate, N-dodecanoyl-L-alanine, sodium lauroyl asparaginate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartic acid, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteinate, N-dodecanoyl-L-cysteine, sodium lauroyl glutamic acid, N-dodecanoyl-L-glutamic acid, sodium lauroyl giutaminate, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L- glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methinoninate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L- phenylalanine, sodium lauroyl proiinate, N-dodecanoyl-L-proline, sodium lauroyl serinate, N-dodecanoyl-L-serine, sodium lauroyl threoninate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophane, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L- valine, N-dodecanoyl-L-sarcosine, sodium capric alaninate, N-decanoyl-L-alanine, sodium capric asparaginate, N-decanoyl-L-asparagine, sodium capric aspartic acid, N-decanoyl-L-aspartic acid, Sodium capric cysteinate, N-decanoyl-L-cysteine, sodium capric glutamic acid, N-decanoyl-L-glutamic acid, sodium capric giutaminate, N-decanoyl-L-glutamine, sodium capric glycinate, N-decanoyl-L-glycine, sodium capric histidinate, N-decanoyl-L-histidine, sodium capric isoleucinate, N-decanoyl-L- isoleucine, sodium capric leucinate, N-decanoyl-L-Ieucine, sodium capric methioninate, N-decanoyl-L-methionine, sodium capric phenylalaninate, N-decanoyl-L-phenylalanine, sodium capric proiinate, N-decanoyl-L-proline, sodium capric serinate, N-decanoyl-L-serine, sodium capric threoninate, N-decanoyl-L-threonine, sodium capric tryptophanate, N-decanoyl-L-tryptophane, sodium capric tyrosinate, N-decanoyl-L-tyrosine, sodium capric valinate, N-decanoyl-L-valine, sodium capric sarcosinate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts of any of the aforementioned compounds; or, e.g., s-2o alkanoyl sarcosinate (e.g., a lauroyl sarcosinate, such as sodium lauroyl sarcosinate) or one of the 20 standard proteinogenic a-amino acids that is acylated with a Cs.2o alkanoic acid), an alkylsaccharide (e.g., a Ci.20 alkylsaccharide, such as, e.g., Cs-i o alkylpolysaccharide like Multitrope™ 1620-LQ-(MV); or, e.g., n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D- maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose mono-dodecanoate, sucrose monotridecanoate, sucrose mono-tetradecanoate, a coco-glucoside, or any of the alkylsaccharides described in US 5,661,130 or in WO 2012 / 112319 which are herein incorporated by reference), a cyclodextrine (e.g., a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, methyl-P- cyclodextrin, hydroxypropyl P-cyclodextrin, or sulfobutylether P-cyclodextrin), N-[8-(2- hydroxybenzoyl)amino]caprylic acid (preferably a N-[8-(2-hydroxybenzoyl)amino]caprylate, more preferably sodium N-[8-(2-hydroxybenzoyl)amino]capry!ate, also referred to as " SNAC"), aN-[8-(2-hydroxybenzoyl)amino]caprylate derivative (preferably a sodium N-[8-(2- hydroxybenzoyl)amino] caprylate derivative), a thiomer (also referred to as a thioiated polymer; may be synthesized, e.g., by immobilization of sulfhydryl bearing ligands on a polymeric backbone of well-established polymers such as, e.g., polyacrylic acid, carboxymethylcellu!ose or chitosan; exemplary thiomers include the thiomers that are described in Laffleur F et al., Future Med Chem. 2012, 4(17):2205-16 (doi: 10.4155 / fmc.l2.165) which is incorporated herein by reference), a mucoadhesive polymer having a vitamin B partial structure (e.g., any of the mucoadhesive polymers described in US 8,980,238 B2 which is incorporated herein by reference; including, in particular, any of the polymeric compounds as defined in any one of claims 1 to 3 of US 8,980,238 B2), a calcium chelating compound (e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate, or polyacrylic acid), cremophor EL (also referred to as " Kolliphor EL"; CAS no. 61791 - 12-6), chitosan, N, N, N-trimethyl chitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, a C2-2O alkanol (e.g., ethanol, decanol, lauryl alcohol, myristyl alcohol, or palmityl alcohol), a Cs-20 alkenol (e.g., oleyl alcohol), a Cs.2o alkenoic acid (e.g., oleic acid), dextran sulfate, diethyleneglycol monoethyl ether (transcutol), l-dodecylazacyclo-heptan-2-one (Azone®), caprylocaproyl polyoxylglycerides (such as, e.g., caprylocaproyl polyoxyl-8 glycerides; available, e.g., as Labrasol® or ACCONON® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, a Cs-2o alkylamine, a Cs-2o alkenylamine (e.g., oleylamine), phosphatidylcholine, a poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, a polysorbate (e.g., polysorbate 80), cholic acid (preferably a cholate, e.g., sodium chlolate), a deoxycholate (e.g., sodium deoxycholate), sodium glycocholate, sodium glycodeoxy cholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethyl ammonium bromide, benzyldimethyl dodecyl ammonium chloride, myristyltrimethyl ammonium chloride, dodecyl pyridinium chloride, decyldimethyl ammonio propane sulfonate, myristyldimethyl ammonio propane sulfonate, palmityldimethyl ammonio propane sulfonate, ChemBetaine CAS, ChemBetaine Oieyl, Nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, hexanoic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebaccate, sodium oleate, urea, lauryl amine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P. glyccyrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyl dodecanol, fenchone, menthone, trimethoxy propylene methyl benzene, a cell-penetrating peptide (e.g., KLAKLAK, polyarginine, penetratin, or HIV-1 Tat), macrogol-15-hydroxystearate (e.g., Solutol HS 15), CriticalSorb (see., e.g., Ilium L et al. J Control Release. 2012; 162(1 ): 194- 200), a taurocholate (e.g., sodium taurocholate), a taurodeoxycholate (e.g., sodium taurodeoxycholate), a sulfoxide (e.g., a (Ci_io alkylHCAo alkyl)-sulfoxide, such as, e.g., decyl methyl sulfoxide, or dimethyl sulfoxide), cyclopentadecaiactone, 8-(N-2-hydroxy-5-chioro- benzoyl)-amino-caprylic acid (also referred to as "5-CNAC"), N-(10-[2- hydroxybenzoyl]amino)decanoic acid (also referred to as " SNAD"), dodecyl-2-N, N- dimethylamino propionate (also referred to as " DDAIP"), D-a-tocopheryl polyethylene glycol- 1000 succinate (also referred to as " TPGS"), and pharmaceutically acceptable salts of the aforementioned compounds. Mixtures of two or more absorption enhancers, including any of the abovedescribed absorption enhancers, can also be used. Moreover, any of the chemical permeation enhancers described in Whitehead K et al. Pharm Res. 2008 Jun;25(6): 1412-9 (particularly any one of those described in Table I of this reference), any one of the modified amino acids disclosed in US 5,866,536 (particularly any one of compounds I to CXXIII, as disclosed in US 5,866,536 which is incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as a disodium salt, an ethanol solvate, or a hydrate of any one of these compounds), any one of the modified amino acids disclosed in US 5,773,647 (particularly any one of compounds 1 to 193, as disclosed in US 5,773,647 which is incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as a disodium salt, an ethanol solvate, or a hydrate of any one of these compounds), any of the nanoparticles described in WO 201 1 / 133198, any of the polymer preparations described in US 2015 / 174076 and / or a hydrogel (e.g., as described in Torres-Lugo M et al. Biotechnol Prog. 2002;

[2460] 18(3):612-6) can likewise be used as absorption enhancer.

[2461]

[0301] The peptides and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, subcutaneous administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In some embodiments, the route of administration is oral or subcutaneous. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[2462]

[0302] In some embodiments, a compound described herein is administered orally to a subject (e.g., as a maintenance therapy) following a treatment regimen with an injectable (e.g., subcutaneous) FcRn inhibitor.

[2463]

[0303] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[2464]

[0304] Peptides provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[2465]

[0305] The exact amount of a peptide required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular peptide, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a peptide described herein.

[2466]

[0306] A peptide or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The peptides or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g, activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[2467]

[0307] Also encompassed by the disclosure are kits (e.g, pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or peptide described herein and a container (e.g, a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or peptide described herein. In some embodiments, the pharmaceutical composition or peptide described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a peptide or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating and / or preventing a disease, disorder, or condition in a subject in need thereof.

[2468]

[0308] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U. S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[2469] Methods of Treatment and Uses

[2470]

[0309] Cyclic peptides provided herein can non-covalently inhibit neonatal fragment crystallizable receptor (FcRn) proteins and are therefore useful in treating FcRn-mediated and immunoglobulin G (IgG)-mediated diseases, including autoimmune and inflammatory diseases.

[2471]

[0310] Provided herein are methods of treating an FcRn-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimer described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an FcRn-mediated disease. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating an FcRn-mediated disease.

[2472] [3H] ‘ ‘FcRn-mediated disease” refers to any disease or condition associated with FcRn protein activity in a subject, including diseases caused or exacerbated by FcRn activity, or for which inhibition of FcRn activity can provide therapeutic benefit. In certain embodiments, the FcRn-mediated disease is an autoimmune disease. In certain embodiments, the FcRn-mediated disease is an inflammatory disease.

[2473]

[0312] Inhibition of FcRn can decrease IgG levels in a subject and can therefore treat diseases and conditions in which autoantibodies are implicated. Provided herein are methods of treating an IgG-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an IgG-mediated disease. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating an IgG-mediated disease.

[2474]

[0313] “IgG-mediated disease” refers to any disease or condition associated with IgG autoantibodies in a subject, including diseases caused or exacerbated by IgG antibodies, or for which decreasing levels of IgG antibodies can provide a therapeutic benefit. In certain embodiments, the IgG-mediated disease is an autoimmune disease. In certain embodiments, the IgG-mediated disease is an inflammatory disease.

[2475]

[0314] Provided herein are methods of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating an autoimmune disease. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments (e.g., for treating an autoimmune disease or inflammatory disease).

[2476]

[0315] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. Autoimmune diseases may be restricted to certain organs or involve a particular tissues in different places. The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. However, cyclic peptides and dimers described herein can provide therapeutic benefit in the treatment of autoimmune diseases.

[2477]

[0316] Autoimmune diseases include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, pemphigus vulgaris, bullous pemphigoid, Goodpasture’s syndrome, autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune hepatitis, Celiac disease, Type 1 diabetes, multiple sclerosis, Sjogren’s syndrome, antiphospholipid syndrome, Wegener’s granulomatosis, polymyositis, dermatomyositis, scleroderma, and autoimmune encephalitis.

[2478]

[0317] Additional exemplary autoimmune diseases include, but are not limited to, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Behcet’s disease, bullous pemphigoid, cardiomyopathy, celiac spruedermatitis herpetiformis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, Degos’ disease, dermatomyositis, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves’ disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, lupus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus (e.g., pemphigus vulgaris), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis / giant cell arteritis, transplant rejection, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis. In some embodiments, the autoimmune disease is bullous pemphigoid, idiopathic thrombocytopenia purpura, myasthenia gravis, pemphigus (e.g., pemphigus vulgaris), and transplant rejection.

[2479]

[0318] Autoimmune diseases can include inflammatory diseases and conditions. The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein, and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation.

[2480]

[0319] Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

[2481]

[0320] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, bums, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g, frostbite, chemical irritants, toxins, scarring, bums, physical injury), vasculitis, vitiligo, and Wegener’s granulomatosis.

[2482]

[0321] In some embodiments, the inflammatory disease is selected from asthma, ulcerative colitis, inflammatory bowel syndrome, allergy (e.g., allergic rhinitis / sinusitis, skin allergies, food allergies, drug allergies, insect allergies), mastocytosis, arthritis (e.g., osteoarthritis, rheumatoid arthritis), and spondyloarthropathies. In some embodiments, the skin allergy is chosen from urticaria, angioedema, and atopic dermatitis.

[2483]

[0322] In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of one or more additional therapeutic agents. In certain embodiments, the additional therapeutic agent is an anti-inflammatory agent. Any inflammatory agent can be used in combination with the compositions disclosed herein. In certain embodiments, the therapeutic agent is rituximab, daclizumab, basiliximab, muronomab-cd3, infliximab, adalimumab, omalizumab, efalizumab, natalizumab, tocilizumab, eculizumab, golimumab, canakinumab, ustekinumab, or belimumab. In certain embodiments, the additional therapeutic agent is leucocyte depleting agent (e.g., B-cell or T-cell depleting agent). Any leucocyte depleting agent can be used in combination with the cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof,. In certain embodiments, the leucocyte depleting agent is a B-cell depleting agent. In certain embodiments, the leucocyte depleting agent is an antibody against a cell surface marker. Suitable cell surface markers include, without limitation, CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80. CD81, CD82, CD83, CD84, CD85, or CD86. The cyclic peptide or dimer provided herein, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, and the additional therapeutic agent(s) can be administered to the subject simultaneously or sequentially, via the same or different route(s) of administration.

[0323] The cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, may also be well suited to rapidly reducing the serum levels of an Fc-containing agent in subject. Such rapid clearance is advantageous in cases where the Fc-containing agent is toxic (e.g., an antibody-drug conjugate or an agent that is immunogenic) because it reduces the exposure of the subject to the drug. Rapid clearance is also advantageous in cases where the Fc-containing agent is an imaging agent that requires a low serum level of the agent to facilitate imaging. Accordingly, in certain embodiments, the cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are used to reduce the serum levels of an Fc-containing agent in subject that has been administered the Fc-containing agent. The serum levels of any Fc-containing agent (e.g., therapeutic or diagnostic agent) can be reduced using the cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Non limiting examples of Fc-containing agents include imaging agents (e.g., labeled antibodies), antibody drug conjugates, or immunogenic agents (e.g., non-human antibodies or immunoadhesins). The cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be administered simultaneously with the Fc-containing agent or sequentially (e.g., before or after the Fc-containing agent).

[2484]

[0324] Furthermore, in diseases or conditions requiring administration of a therapeutic agent, the subject will often develop antibodies (e.g., anti-drug antibodies) against the therapeutic agent, which, in turn, prevent the therapeutic agent from being available for its intended therapeutic purpose or cause an adverse reaction in the subject. Accordingly, the cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can also be used to remove antibodies (e.g, anti-drug antibodies) against the therapeutic agent that develop in a subject.

[2485]

[0325] The cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can also be used in combination with the therapeutic protein to enhance the benefit of the therapeutic protein by reducing the levels of IgG; wherein, IgG antibodies are responsible for the decreased bioavailability of a therapeutic protein. In certain embodiments the instant disclosure provides a method of treating a disorder resulting from an immune response to a clotting factor comprising administering to a subject a therapeutically effective amount of the cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof,. Suitable clotting factors include, without limitation, fibrinogen, prothrombin, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, factor XIII, or von Willebrand's factor. This method may be used to regulate or treat, or prevent an immune response to a clotting factor in a patient suffering, e.g., from hemophilia A or hemophilia B. In certain embodiments, the method may be used to regulate or treat an immune response to, e.g., therapeutic erythropoietin in a patient suffering from pure red cell aplasia (PRC A).

[2486]

[0326] FcRn is responsible for transporting maternal antibodies across the placenta to the fetus in a pregnant woman. Accordingly, if a pregnant female is administered an Fc-containing agent (e.g., a therapeutic antibody), the agent may come in contact with the fetus as a result of the FcRn-mediated transport across the placenta. To avoid any potential deleterious effect of the Fc-containing agent on fetal development, it would be advantageous to block FcRn function. Accordingly, the instant disclosure provides a method of preventing placental transfer of an Fc-containing agent (e.g., a therapeutic antibody) to the fetus in a pregnant woman, the method comprising administering to the woman cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof,, either simultaneously or sequentially (prior or post) with the Fc-containing agent.

[2487]

[0327] The FcRn antagonist compositions disclosed herein can also be used to treat inflammatory disorders including, but not limited to, asthma, ulcerative colitis and inflammatory bowel syndrome allergy, including allergic rhinitis / sinusitis, skin allergies (urticaria / hives, angioedema, atopic dermatitis), food allergies, drug allergies, insect allergies, mastocytosis, arthritis, including osteoarthritis, rheumatoid arthritis, and spondyloarthropathies.

[2488]

[0328] Successful implementation of gene therapy for the treatment of a disease or condition may be hampered by the development of antibodies specific to the therapeutic protein encoded by the transgene as well as possibly to the vector used to deliver the transgene. Accordingly, the cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be administered in combination with gene therapy to enhance the benefit of the encoded therapeutic protein by reducing the levels of IgG. These methods are particularly useful in situations where IgG antibodies are responsible for the decreased bioavailability of a gene therapy vector or the encoded therapeutic protein. The gene therapy vector may be, e.g., a viral vector such as adenovirus and adeno-associated virus. Diseases that can be treated using gene therapy include, but are not limited to, cystic fibrosis, hemophilia, PRCA, muscular dystrophy, or lysosomal storage diseases, such as, e.g., Gaucher's disease and Fabry's disease.

[2489]

[0329] Also provided herein are methods of inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in inhibiting FcRn in vitro or in vivo. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for inhibiting FcRn in a subject.

[2490]

[0330] In certain embodiments, the inhibiting comprises non-covalently inhibiting FcRn. In certain embodiments, the inhibiting comprises covalently inhibiting FcRn.

[2491]

[0331] As used herein the term “inhibit,” “inhibition,” or “inhibiting” in the context of proteins, for example, in the context of FcRn proteins, refers to a reduction in the activity of the protein or a downstream effect. In some embodiments, the term refers to a reduction in the level of protein activity (e.g., FcRn activity) to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline or reference level of protein activity. In some embodiments, the term refers to a reduction of the level of protein activity (e.g., FcRn activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, of an initial level, which may, for example, be a baseline level of protein activity.

[2492]

[0332] “Covalently inhibiting,” “covalent inhibition,” “covalently inhibit” and the like, refers to inhibition of target protein (e.g., FcRn) activity resulting from covalent binding of an agent (e.g., a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof) to the target protein. In certain embodiments, the agent binds to an amino acid residue (e.g., an amino acid side chain) of the target protein. Covalent inhibitors can be orthosteric or allosteric. “Orthosteric” covalent inhibitors covalently bind to the active site of the target protein, whereas “allosteric” covalent inhibitors can bind elsewhere on the protein surface.

[2493]

[0333] “Non-covalently inhibiting,” “non-covalent inhibition,” “non-covalently inhibit” and the like, refers to inhibition of target protein (e.g., FcRn) activity resulting from non-covalent binding of an agent (e.g., a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof) to the target protein. In certain embodiments, the agent binds to an amino acid residue (e.g., an amino acid side chain) of the target protein. Non-covalent inhibitors can be orthosteric or allosteric. “Orthosteric” non-covalent inhibitors non-covalently bind to the active site of the target protein, whereas “allosteric” non-covalent inhibitors can bind elsewhere on the protein surface.

[2494]

[0334] Also provided herein are methods of decreasing IgG levels in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide or dimer provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in decreasing IgG levels in a subject. In another aspect, provided herein are uses of cyclic peptides and dimers described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for decreasing IgG levels in a subject.

[2495]

[0335] In certain embodiments, the decrease in IgG levels in the subject is a reduction in the level of IgG in the subject which is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of an initial level (e.g., before administration of an FcRn inhibitor).

[2496]

[0336] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease, disorder, or condition.

[0337] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, providing or otherwise introducing a peptide described herein, or a composition thereof, in, to or on a subject.

[2497]

[0338] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[2498]

[0339] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[2499]

[0340] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[2500]

[0341] An “effective amount” of a peptide described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a peptide described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular peptide, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a peptide described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a peptide described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for non-covalently inhibiting FcRn and / or decreasing the levels of IgG (e.g., in a subject or in a cell in vitro).

[2501]

[0342] A “therapeutically effective amount” of a peptide described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a peptide means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with FcRn activity) in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for non-covalently inhibiting FcRn and / or decreasing the levels of IgG in a subject.

[0343] A “prophylactically effective amount” of a peptide described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a peptide means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a disease, disorder, or condition (e.g., a disease, disorder, or condition associated with FcRn activity) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for non-covalently inhibiting FcRn and / or decreasing the levels of IgG.

[2502]

[0344] “Neonatal fragment crystallizable receptor” (also “FcRn”, “IgG receptor FcRn large subunit p51”, or “Brambell receptor”) refers to the protein that in humans is encoded by the FCGRT gene. See Uniprot accession number P55899 for human FcRn.

[2503] EXAMPLES

[2504] FcRn Inhibition and Biological Data

[2505]

[0345] Compounds of the present disclosure are evaluated in protein-protein interaction assays, which are expected to show that the compounds of the present disclosure bind to and / or inhibit FcRn.

[2506] Table 3

[2507] Abbreviation Definition

[2508] AA Amino acid

[2509] Ac2O Acetic anhydride

[2510] Alloc Allyoxycarbonyl

[2511] ACN Acetonitrile

[2512] Acm Acetaminomethyl

[2513] Bop Benzotriazol-l-yloxytris(dimethylamino)phosphonium

[2514] Boc Tert-butoxy -carbonyl

[2515] DMF N, N-Dimethylformamide

[2516] DCM Dichloromethane

[2517] DIEA Diisopropylethylamine

[2518] DIC Diisopropylcarbodiimide

[2519] Dde 1 -(4,4-dimethyl-2,6-dioxocyclohex- 1 -ylidenejethyl

[2520] DMAP 4-Dimethylaminopyridine

[2521] DBU l,8-Diazabicyclo[5,4,0]undec-7-ene

[2522] EDT Ethanedithiol

[2523] ESI Electrosprayionization

[2524] EDC. HC1 1 -Ethy 1-3 -(3 -dimethy llaminopropy l)carbodiimide hydrochloride

[2525] Fmoc Fluorenylmethyloxycarbonyl

[2526] g Gram

[2527] h Hour

[2528] H2O Water

[2529] HFIP Hexafluoroisopropanol

[2530] HOBt 1 -Hydroxybenzo triazole

[2531] HATU 2-(7-Azabenzotriazol- 1 -yl)-N, N, N’, N’ -tetramethyluronium hexafluorophosphate HBTU 2-( Ih-benzotriazole- 1 -y 1) - 1, 1,3,3 -tetramethyluronium hexafluorophosphate

[2532] HOSU N-Hydroxy succinimide

[2533] HC1 Hydrogen chloride

[2534] I2 Iodine

[2535]

[2536] LC / MS Liquid chromatography / mass spectrometry Abbreviation Definition

[2537] L Liter

[2538] MeOH Methanol

[2539] mL Milliliter

[2540] min Minute

[2541] mm Millimeter

[2542] mmol Millimolar

[2543] M Molar per liter

[2544] m / z mass-to-charge ratio

[2545] nm Nanometre

[2546] NsCl 2-Nitrobenzenesulfonyl chloride

[2547] NMM 4-Methylmorpholine

[2548] OA11 Allyl

[2549] Oxyma Ethyl cyanoglyoxylate-2 -oxime

[2550] Pip Piperidine

[2551] Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

[2552] PyAOP ((7-Azabenzotriazol-l-yl)oxy)tris(pyrrolidino)phosphonium hexafluorophosphate PyBOP (Benzotriazol- 1 -yl-oxy)tripyrrolidinophosphonium hexafluorophosphate

[2553] Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium

[2554] RP-HPLC Reverse phase high-performance liquid chromatography

[2555] RT room temperature

[2556] SPPS Solid Phase peptide synthesis

[2557] tBu Tert-butyl

[2558] TFA Trifluoroacetic acid

[2559] TEA N, N-Diethylethanamine

[2560] Trt Trityl

[2561] THF Tetrahydrofuran

[2562] TEAP Triethylammonium phosphate

[2563] TCEP. HC1 Tris(2-carboxyethyl)phosphine Hydrochloride

[2564] UV Ultraviolet

[2565] Vc Vitamin C

[2566] V volume

[2567] pL Micro liter

[2568] pm Micrometre

[2569]

[2570] rpm Revolutions Per Minute

[2571] Example 1. Synthesis of building blocks for both SPPS and off-bead synthesis

[2572] Scheme 1. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(ethylamino)-2- oxoethyl)glycine (Fmoc-(2-(ethylamino)-2-oxoethyl)glycine)

[2573]

[2574] Fmoc-(2-(ethylamino)-2-oxoethyl)glycine

[0346] Step 1: A mixture of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (15 g, 36.5 mmol) and Ethylamine hydrochloride (3.57 g, 43.8 mmol) in 150 m DMF was cooled to 0-10°C. Then NMM (12.0 m, 109.5 mmol) and HATU (13.86 g, 36.5 mmol) were added into the mixture and stirred at RT for 2.5 h. The mixture was quenched by 5%H3PO4 (100 mb) and extracted with DCM (2 x 150 mb). The combined organic layer were washed with 5%H3PO4 (lOOmb) and saturated sodium chloride solution (100 mb), dried over Na2SO and fdtered. The fdtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(ethylamino)-2-oxoethyl)glycinate. MS ESI calculated for C25H30N2O5 [M+H]+ 438.52, found 438.50.

[0347] Step 2: Tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(ethylamino)-2-oxoethyl)glycinate (15.99 g, 36.5 mmol) was treated with 70%TFA / DCM (100 mL) at RT for 2 h. The mixture was concentrated under reduced pressure and extracted with 50% DCM / H2O (2 x lOOmL). The combined organic layer were washed with saturated sodium chloride solution (100 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-(ethylamino)-2-oxoethyl)glycine. MS ESI calculated for C21H22N2O5 [M+H]+ 382.42, found 382.4.

[2575] Scheme 2. Synthesis of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4-nitrophenyl)sulfonamido) ethoxy)ethyl)amino)-2-oxoethyl)glycine (N-Fmoc-(2-((2-(2-((4-nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycine)

[2576]

[2577] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-

[2578]

[2579] N-(2-((2-(2-((4-nitrophenyl)sulfonamido) ethoxy)ethyl)amino)-2-oxoethyl)glycine

[0348] Step 1: A mixture of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (50 g, 244.8 mmol) and TEA (51 mL, 367.6 mmol) in DCM (300 mL) was cooled to 0-10°C. NsCl (59.7 g, 293.7 mmol) in DCM (80 mL) was added slowly and the mixture was stirred at RT for 1.5 h. Then the reaction solution was quenched by 5%H3PC>4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5%H3PC>4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl-(2-(2-((4-nitrophenyl)sulfonamido)ethoxy)ethyl)-carbamate. MS ESI calculated for C15H23N3O7S [M+H]+ 389.42, found 389.4.

[2580]

[0349] Step 2: tert-butyl-(2-(2-((4-nitrophenyl)sulfonamido)ethoxy)ethyl)-carbamate (95.3 g, 244.8 mmol) was cooled to 0-10°C. Then 4N HC1 / EA (600 mL) was added and stirred at RT for 1 h. A white solid precipitated and filtered. Then the solid was washed with EA (3 x 100 mL) and dried in vaccum to afford N-(2-(2-aminoethoxy)ethyl)-4-nitrobenzenesulfonamide. MS ESI calculated for C10H15N3O5S [M+H]+ 289.42, found 289.4.

[2581]

[0350] Step 3: A mixture of Fmoc-N-(tert-butyloxycarbonylmethyl)-glycine (46 g, 116.28 mmol) andN-(2-(2-aminoethoxy)ethyl)-4-nitrobenzenesulfonamide (34 g, 122.4 mmol) in DMF (300 mL) was cooled to 0-10°C. Then NMM (40 mL, 367.2 mmol) and HATU (13.86 g, 36.5 mmol) were added into the mixture and stirred at RT for 2.5 h. The mixture was quenched by 5%H3PC>4 (200 mL) and extracted with DCM (2 x 300 mL). The combined organic layer were washed with 5%H3PC>4 (200 mL) and saturated sodium chloride solution (200 mL), dried over TsfeSCL and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4- nitrophenyl)sulfonamido) ethoxy)ethyl)amino)-2-oxoethyl)glycinate. MS ESI calculated for C33H38N4O10S [M+H]+ 682.23, found 682.2.

[2582]

[0351] Step 4: tert-butyl-N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4-nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycinate (83.5 g, 122.4 mmol) was treated with 70%TFA / DCM (500 mL) at RT for 2 h. The mixture was concentrated under reduced pressure and extracted with 50%DCM / H2O (2 x 250mL). The combined organic layer were washed with saturated sodium chloride solution (200 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(2-((2-(2-((4-nitrophenyl)sulfonamido)ethoxy)ethyl)amino)-2-oxoethyl)glycine. MS ESI calculated for C29H30N4O10S [M+H]+ 626.64, found 626.6.

[2583] Scheme 3. Synthesis of (S)-3-(22-(tert-butoxycarbonyl)-43,43-dimethyl-10, 19,24, 41-tetraoxo- 3,6,12,15,42-pentaoxa-9,18,23-triazatetratetracontanamido)pentanedioic acid (tBuO-Ste- Glu(AEEA-AEEA-3-aminopentanedioic acid)-OtBu)

[2584] 1. 20% Pip / DMF 2. tBuO-Ste-Glu(AEEA-AEEA-OH)-OtBu, PyAop, HOBT and DIEA in DMF Step 2

[2585]

[2586] tBuO-Ste-Glu(AEEA-AEEA-3-aminopentanedioic acid)-OtBu

[0352] Step 1: CTC Resin (10 mmol, 14.3 g) and Fmoc-betaGlu-OH (10 mmol, 3.7 g) in DMF ( 70 mL) were added to a clear glass reactor. DIEA (40 mmol) was added slowly. Reaction was performed at RT for 3 h while a stream of nitrogen bubbled through it. Then MeOH (15 mL) was added to cap resin for 0.5 h. Peptide resin was washed with DMF (100 mL) twice.

[2587]

[0353] Step 2: Peptide resin was treated with 20%Pip / DMF for 0.5 h to remove Fmoc group and washed with DMF (100 mL) for 5 times. tBuO-Ste-Glu(AEEA-AEEA-3 -aminopentanedioic acid)-OtBu (16 mmol) was activated with PyAop (16 mmol), HOBT (16 mmol) and DIEA (32 mmol) in DMF for 5-15 mins. Then activated solution was added to the reactor for 2 h and washed with DMF (100 mL) x 5 and MeOH (100 mL) x 4. The peptide resin was dried under vacuum overnight.

[2588]

[0354] Step 3: The dried peptide resin was treated with 30%HFIP / DCM for 1.5 h and filtered. The filtrate was concentrated under reduced pressure to afford tBuO-Ste-Glu(AEEA-AEEA-3-aminopentanedioic acid)-OtBu. MS ESI calculated for C48H86N4O16 [M+H]+ 975.23, found 975.76. Scheme 4. Synthesis of 25,43-di-tert-butyl l-(2,5-dioxopyrrolidin-l-yl) (S)-2-(2-((2,5- dioxopyrrolidin-l-yl)oxy)-2-oxoethyl)-4,13,22,27-tetraoxo-6,9,15,18-tetraoxa-3,12,21,26-tetraazatritetracontane-l,25,43-tricarboxylate

[2589] 25,43-di-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) (S)-2-(2-((2,5-dioxopyrrolidin-1-yl)oxy)- 2-oxoethyl)-4, 13,22, 27-tetraoxo-6, 9, 15,18-tetraoxa-3, 12,21,26-tetraazatritetracontane-

[2590]

[2591] 1,25,43-tricarboxylate

[0355] To a solution of (S)-3-(22-(tert-butoxycarbonyl)-43,43-dimethyl-10,19,24,41-tetraoxo- 3,6,12,15,42-pentaoxa-9,18,23-triazatetratetracontanamido)pentanedioic acid (5 g, 5.13 mmol) in 50 mL DMF was added EDC. HC1 (2.95 g, 15.4 mmol) and HOSU (1.75 g, 15.4 mmol). Then stirred overnight at RT. H2O (100 mL) was added and extracted with DCM (2 x 100 mL). The combined organic layer were dried over NaSO4 and filtered, solvent was removed under reduced pressure. Then dissolved in ACN (50 mL) and lyophilized to afford 25,43-di-tert-butyl l-(2,5-dioxopyrrolidin-l-yl) (S)-2-(2-((2,5- dioxopyrrolidin- l-yl)oxy)-2-oxoethyl)-4, 13,22,27-tetraoxo-6,9, 15, 18-tetraoxa-3, 12,21,26-tetraazatritetracontane- 1,25, 43 -tricarboxylate. MS ESI calculated for C56H92N6O20 [M+H]+ 1169.37, found 1169.4.

[2592] Scheme 5. Synthesis of 4-(4-(((((9H-fluoren-9-yl)methoxy)carbonyl)(4-((N-methyl-4- nitrophenyl)sulfonamido)butyl)amino)methyl)-3-methoxyphenoxy)butanoic acid

[2593]

[2594]

[0356] Step 1: To a solution of tert-butyl (4-(methylamino)butyl)carbamate (20 g, 98.9 mmol) and TEA (20.8 mL, 148.35 mmol) in DCM (100 mL) cooled to 0-10°C was added NsCl (24.4 g, 108.8 mmol) which was dissolved by DCM (50 mL) slowly. The mixture was stirred at 25-35°C for 4 hours. Then quenched by 5%H3PC>4 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layer were washed with 5%H3PO4 (200 mL) and saturated sodium chloride solution (200 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-((N-methyl-4-nitrophenyl) sulfonamido) butyl)carbamate. MS ESI calculated for CieEhsNsOeS [M+H]+387.45, found 387.6.

[2595]

[0357] Step 2: Tert-butyl (4-((N-methyl-4-nitrophenyl)sulfonamido)butyl)carbamate (38.3 g, 98.9 mmol) was treated with 4N HC1 / EA (150 mL) at RT for 1 h, then ethyl ether (200 mL) was added, a white solid precipitated and filtered. Then the solid was washed with EA (3 x 100 mL) and dried in vacuum to afford N-(4-aminobutyl)-N-methyl-4-nitrobenzenesulfonamide. MS ESI calculated for C11H17N3O4S [M+H]+287.33, found 287.3.

[2596]

[0358] Step 3: To a solution of 4-(4-formyl-3-methoxyphenoxy)butanoic acid (13.1 g, 54.9 mmol) and N-(4-aminobutyl)-N-methyl-4-nitrobenzenesulfonamide (19 g, 65.9 mmol) in MeOH: H2O = 10: 1 (130 mL) was added DIEA (28.7 mL, 164.7 mmol) and stirred at 0°C for 0.5 hour. NaBEL (4.16 g, 109.8 mmol) in H2O (18 mL) was added slowly and the solution was stirred at RT for 4 hours. Con. HCl was added to adjust pH 7-8. Then the mixture was concentrated under reduced pressure to afford 4-(3-methoxy-4-(((4-((N-methyl-4-nitrophenyl) sulfonamido) butyl)amino) methyl)phenoxy)butanoic acid. MS ESI calculated for C23H3iN3O8S [M+H]+509.57, found 509.5.

[2597]

[0359] Step 4: 4-(3-methoxy-4-(((4-((N-methyl-4-nitrophenyl) sulfonamido) butyl) amino)methyl)phenoxy)butanoic acid (28 g, 54.9 mmol) was dissolved in THE: H2O = 2: 1 (250 mL). The solution was adjusted to pH 8-9 by a saturated aqueous solution of ISfeCOs. Lmoc-OSu (37 g, 109.8 mmol) was added and stirred at RT for 16 hours. Then adjusted pH 3-4 by 5%H3PO4 and extracted with DCM (2 x 300 mL). The combined organic layer were washed with saturated sodium chloride solution (20 mL), dried over ISfeSCL and fdtered. The fdtrate was concentrated under reduced pressure and purified by reversed phase HPLC to afford 4-(4-(((((9H-fluoren-9-yl)methoxy)carbonyl)(4-((N-methyl-4-nitrophenyl)sulfonamido)butyl)amino)methyl)-3-methoxyphenoxy)butanoic acid. MS ESI calculated for C38H41N3O10S [M+H]+731.8, found 732.

[2598] Scheme 6. Synthesis of 4-(4-(((((9H-fluoren-9-yl)methoxy)carbonyl)(4-(trimethyl-X4-azaneyl)butyl)amino)methyl)-3-methoxyphenoxy)butanoic acid

[2599] Stepl Step2

[2600]

[2601]

[0360] Step 1: To a solution of tert-butyl (4-aminobutyl)carbamate (17.5 g, 93.1 mmol) in ACN (105 mL) was added K2CO3 (51.5 g, 372.4 mmol) and CH3I (29 mL, 46.5 mmol) slowly, then the mixture was stirred at RT for 16 hours. H2O (42 mL) was added and treated by ultrasonic waves for 10 min. The supernatant was lyophilized to afford tert-butyl (4-(trimethyl-X4-azaneyl)butyl)carbamate. MS ESI calculated for CI2H27N2O2 [M+H]+231.36, found 231.3.

[2602]

[0361] Step 2: Tert-butyl (4-(trimethyl-X4-azaneyl)butyl)carbamate (21.5 g, 93.1 mmol) was treated with 4N HC1 / EA (200 mL) at RT for 3.5 hours. A white solid precipitated and filtered. Then the solid was washed with EA (3 x 100 mL) and dried in vacuum to afford 4-(trimethyl-X4-azaneyl)butan-l -amine. MS ESI calculated for C7HI9N2[M+H]+131.24, found 131.2.

[2603]

[0362] Step 3: To a solution of 4-(4-formyl-3-methoxyphenoxy)butanoic acid (18.49 g, 77.6 mmol) and 4-(trimethyl-X4-azaneyl)butan- 1 -amine (12.2 g, 93.1 mmol) in MeOH: H2O = 10:1 (165 mL) was added DIEA (40.5 ml, 232.8 mmol) and stirred at 0°C for 0.5 hours. NaBEL (5.87 g, 155.2 mmol) in H2O (25 mL) was added slowly and the solution was stirred at RT for 4 hours. Con. HCl was added to adjust pH 7-8. Then the mixture was concentrated under reduced pressure to afford 4-(3-methoxy-4-(((4-(trimethyl-X4-azaneyl)butyl)amino)methyl)phenoxy)butanoic acid. MS ESI calculated for C19H33N2O4 [M+H]+353.48, found 353.5.

[2604]

[0363] Step 4: 4-(3-methoxy-4-(((4-(trimethyl-X4-azaneyl) butyl)amino)methyl)phenoxy) butanoic acid (27.4 g, 77.6 mmol) was dissolved by THF: H2O = 2: 1 (200 mL). The mixture was adjusted to pH 8-9 by a saturated aqueous solution of Na2CC>3 Fmoc-OSu (37 g, 109.8 mmol) was added and stirred at RT for 16 hours. The mixture was adjusted to pH=3-4 by 5%fLPO4 and extracted with DCM (2 x 300 mL). The combined organic layer were washed with saturated sodium chloride solution (20 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure and purified by reversed phase HPLC to afford 4-(4-((((( 9H-fluoren-9-yl)methoxy)carbonyl)(4-(trimethyl-X4-azaneyl) butyl) amino)methyl) -3 -methoxyphenoxy jbutanoic acid. MS ESI calculated for C34H43N2O6 [M+H]+575.73, found 575.7.

[2605] Scheme 7. Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxypyridin-3-yl)propanoic acid hydrochloride Salt

[2606] Step 1 OMe Step 2

[2607] OH

[2608] 6M HCI Zn, PdCI2, Xphos DMF dioxane

[2609]

[2610]

[0364] Step 1: A solution of compound 2 (5 g, 11 mmol, 1.00 eq) in DMF (30 mL) was added dropwise to Zn (3.6 g, 55 mol, 5.00 eq) in DMF (2 mL) under N2 atmosphere. The mixture was stirred at 25 °C and was monitored by TLC. The resulting intermediate mixture in DMF solution was used directly by adding to a solution of compound 1 (1.66 g, 8.8 mmol, 1.00 eq), PdCF (78 mg, 0.44 mmol, 0.05 eq) and XPhos (420 mg, 0.88 mmol, 0.10 eq) in DMF (16 mL). The mixture was stirred at 45 °C for 16 hrs under N2 atmosphere. The reaction mixture was added water and EtOAc and filtered. The aqueous phase was back extracted with EtOAc. The combined organic phases were washed with water, brine, concentrated and taken to the next step.

[0365] Step 2: Intermediate 3 in EtOAc was added 0.5 M HC1 aqueous solution, stirred and resulting solid product filtered. The aqueous phase was separated and extracted with EtOAc. The filter cake and aqueous phase was dried by lyophilization to give compound 3 as a yellow solid. MS ESI calculated for C24H22N2O5 [M+H]+ 419.5, found 419.4.

[2611]

[0366] The following were prepared in a method similar to Synthetic Scheme 7:

[2612] Intermediate Measured

[2613] No. Structure Name Mass Observed Ion (Da)

[2614] F

[2615] (S)-2-((((9H-fluoren-9- F^O 0 yl)methoxy)carbonyl)amino)-3-(4- 7-1 455 [M+H] (difluoromethoxy )py ridin-3 - HN_ yl)propanoic acid

[2616] N Fmoc

[2617] 0 (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(4- 7-2 433 [M+H] methoxy-6-methylpyridin-3 - ' NHN'c Fmoc yl)propanoic acid

[2618] ^0 0 (S)-2-((((9H-fluoren-9- 7-3 yl)methoxy)carbonyl)amino)-3-(4- 433 [M+H] ethoxypy ridin-3 -yl)propanoic acid

[2619] HN„

[2620] N Fmoc

[2621] ^0 0

[2622] (S)-2-((((9H-fluoren-9- 7-4 yl)methoxy)carbonyl)amino)-3-(4,5- 449 [M+H] dimethoxypy ridin-3 -y l)propanoic acid

[2623] MHN'Fmoc

[2624] O (S)-2-((((9H-fluoren-9- 7-5 yl)methoxy)carbonyl)amino)-3-(4- 447 [M+H] isopropoxypy ridin-3 -y l)propanoic acid

[2625] HN.

[2626] N Fmoc

[2627] '''l / 0 (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(4- 7-6 432 [M+H] (dimethylamino)pyridin-3-yl)propanoic

[2628] HN.

[2629] N Fmoc acid

[2630] 1 ° (S)-2-((((9H-fluoren-9- 7-7 yl)methoxy)carbonyl)amino)-3-(4- 403 [M+H] HKk methylpyridin-3-yl)propanoic acid

[2631] N Fmoc

[2632] O

[2633] (S)-2-((((9H-fluoren-9- 7-8 yl)methoxy)carbonyl)amino)-3-(2- 403 [M+H] methylpyridin-3-yl)propanoic acid

[2634] N Fmoc

[2635] O

[2636] (S)-2-((((9H-fluoren-9- 7-9 yl)methoxy)carbonyl)amino)-3-(4- 404 [M+H] methylpyrimidin-5-yl)propanoic acid

[2637] N Fmoc

[2638] 0

[2639] (S)-2-((((9H-fluoren-9- y l)methoxy )carbony l)amino)-3 - 7-10 N V / VN ^ HNT_X°H429 [M+H] (imidazo [ 1,2-a]pyrimidin-3 - / \ Fmoc

[2640] N^j / yl)propanoic acid

[2641]

[2642] (S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(6,7- [M+H] dihydro-5H-pyrrolo [ 1,2-a]imidazol-3 - yl)propanoic acid

[2643]

[2644] Scheme 8. Synthesis of (2S)-3-[5-[(dimethylamino)methyl]-2-furyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[2645]

[2646]

[0367] Step 1: A mixture of Zn (6.59 g, 100 mmol) in DMF (10.0 mL) was added methyl (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-iodo-propanoate (13.0 g, 28.8 mmol) in DMF (100 mL) under N2 atmosphere and stirred at 25 °C for 2 hrs. The [(2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (14.8 g, crude) as gray liquid was used into the next step without further purification.

[2647]

[0368] Step 2: To a solution of 5-bromofuran-2-carbaldehyde (3.00 g, 17.1 mmol) in DMF (20.0 mL) was added PdCL (152 mg, 857 pmol), XPhos (817 mg, 1.71 mmol) and [(2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (11.5 g, 22.2 mmol) under N2 atmosphere. The mixture was stirred at 45 °C for 16 hrs under N2 atmosphere. The reaction mixture was partitioned between water 100 mL and EtOAc 80.0 mL, then the mixture was filtered. The organic phase was separated. The aqueous phase was extracted with EtOAc 160 mL (80 mL * 2). The combined organic layers were washed with water 300 mL (100 mL * 3) and brine 100 mL (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, hexane: ethyl acetate = 1: 0 to 0: 1) to afford methyl (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(5-formyl-2-furyl)propanoate (5.09 g, 11.5 mmol, 67.1% yield). MS ESI calculated for C24H21NO6 [M+Na]+442.14, found 442.1.

[2648]

[0369] Step 3: To a solution of methyl (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(5-formyl-2-furyl)propanoate (5.09 g, 11.5 mmol) and N-methylmethanamine (1.45 mL, 11.5 mmol) in MeOH (100 mL). Then the mixture was added NaBHsCN (722 mg, 11.5 mmol) and AcOH (690 mg, 11.5 mmol, 657 pL) at 0 °C. The mixture was stirred at 25 °C for 15 hrs. The reaction mixture was diluted with water 200 mL and extracted with EtOAc 300 mL (150 mL * 2). The combined organic layers were washed with IN HC1 aqueous solution 600 mL (100 mL * 6). The aqueous phase was produced by freeze-drying to afford methyl (2S)-3-[5-[(dimethylamino)methyl]-2-furyl]-2-(9H-fluoren-9- ylmethoxycarbonylamino)propanoate (3.34 g, crude). MS ESI calculated for C26H28N2O5 [M+H]+449.20, found 449.2.

[2649]

[0370] Step 4: To a solution of methyl (2S)-3-[5-[(dimethylamino)methyl]-2-furyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoate (3.34 g, 6.88 mmol) in dioxane (33.0 mL) and 6 M HC1 aqueous solution (33.0 mL). The mixture was stirred at 60 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove dioxane (33 mL). The mixture was produced by freeze-drying to afford the residue. The residue was purified by reversed-phase HPLC (0.05% HC1 condition) to afford (2S)-3-[5-[(dimethylamino)methyl]-2-furyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.573 g, 3.26 mmol, 47.3% yield). MS ESI calculated for C25H26N2O5 [M+H]+435.18, found 435.1.

[2650]

[0371] The following was prepared in a method similar to Synthetic Scheme 8:

[2651] Intermediate Measured Structure Nam Observed No. e Mass Ion (Da)

[2652] / ft (S)-2-((((9H-fluoren-9- — N <5 A yl)methoxy)carbonyl)amino)-3-(5- 8-1 \ _ / 451 [M+H] M HNk ((dimethylamino)methyl)thiophen-2-

[2653]

[2654] Fmoc yl)propanoic acid

[2655] Scheme 9. Synthesis of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3,4dihydro-2H-pyrido[4,3-b][l,4]oxazin-8-yl)propanoic acid

[2656]

[2657]

[0372] Step 1: Amixture of 3-amino-5-bromo-pyridin-4-ol (14.1 g, 74.5 mmol) and K2CO3 (25.7 g, 186 mmol) in DML (350 mL) was degassed and purged with N2 for 3 times, and then was added 2-chloroacetyl chloride (9.26 g, 82.0 mmol, 6.53 mL) at 0°C, the mixture was stirred at 25 °C for 24 hrs under N2 atmosphere. The reaction mixture was added H2O 1000 mL, the mixture was stirred at 25 °C for 1 hr, and then filtered and solid was concentrated under reduced pressure to afford 8-bromo-2H-pyrido[4,3-b][l,4]oxazin-3(4H)-one without further purification (8.00 g, 30.9 mmol, 41.4% yield). MS ESI calculated for C7H5BrN2O2 [M+H]+228.96, found 228.8.

[2658]

[0373] Step 2: To a solution of 8-bromo-4H-pyrido[4,3-b][l,4]oxazin-3-one (8.16 g, 35.6 mmol) in THE (120 mL) was added BH3THF (1.00 M, 106 mL) at 5 °C under N2. The mixture was stirred at 60 °C for 12 hrs under N2. The mixture was added BH3THF (1.00 M, 106 mL) at 5 °C under N2. The mixture was stirred at 60 °C for another 12 hrs under N2. The reaction mixture was quenched by addition MeOH 60 mL at 0 °C, the resulting mixture was stirred at 60 °C for 2 hrs, and then concentrated under reduced pressure to give a residue. The residue was diluted with 500 mL 1 M HC1 aqueous solution and extracted with 500 mL EtOAc. The aqueous phase was adjusted pH = 8-9 with Na2CO3(solid) and extracted with EtOAc 1500 mL (500 mL *3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to afford 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][l,4]oxazine (3.44 g, 14.3 mmol, 40.1% yield). MS ESI calculated for C7H7BrN2O [M+H]+214.98, found 214.8.

[2659]

[0374] Step 3: To a solution of 8-bromo-3,4-dihydro-2H-pyrido[4,3-b][l,4]oxazine (3.44 g, 14.3 mmol) in DCM (30.0 mL) was added (Boc)2O (4.68 g, 21.4 mmol, 4.92 mL) and TEA (5.94 mL, 42.9 mmol). The mixture was stirred at 25 °C for 18 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexane / ethyl acetate = 100 / 0 ~ 30 / 70) to afford tert-butyl 8-bromo-2,3-dihydro-4H-pyrido[4,3-b][l,4]oxazine-4-carboxylate (3.50 g, 10.9 mmol, 76.8% yield). MS ESI calculated for Ci2Hi5BrN2O3[M+H]+315.03, found 315.0.

[2660]

[0375] Step 4: To a solution of methyl (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-iodo-propanoate (2.54g, 5.64 mmol) in DME (10.0 mL) was added Zn (1.54 g, 23.5 mmol) and I2(238 mg, 941 pmol) under N2. The mixture 1 was stirred at 25 °C for 1 hr. To a solution of tert-butyl 8-bromo-2,3-dihydropyrido[4,3-b][l,4]oxazine-4-carboxylate (1.50 g, 4.70 mmol) in DME (10 mL) was added PdCl2(83.469 mg, 470 pmol) and SPhos (96.6 mg, 235 pmol) under N2. Then was added mixture 1 under N2. The mixture was stirred at 40 °C for 12 hrs under N2. The reaction mixture was added water 45 ml and EtOAc 25 mL stirred at 25 °C for another 0.1 hr, then filtered, the filtrate was extracted with EtOAc 60 mL (30 mL * 2). The combined organic layers were washed with water 90 mL (45mL * 2), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, hexane / ethyl acetate = 100 / 0 ~ 85 / 15) to afford tert-butyl (S)-8-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)-2,3-dihydro-4H-pyrido[4,3 b][l,4]oxazine-4-carboxylate (3.70 g, crude). MS ESI calculated for C3IH33N3O7[M+H]+560.24, found 560.2.

[2661]

[0376] Step 5: To a solution tert-butyl 8-[(2S)-2-(9H-fluoren-9-yhnethoxycarbonylamino)-3-methoxy-3-oxopropyl]-2,3-dihydropyrido[4,3-b][l,4]oxazine-4-carboxylate (3.70 g, 6.57 mmol) in i-PrOH (60.0 mL) and THF (40.0 mL) was added CaCl2(11.6 g, 105 mmol), and then LiOH H2O (1.10 g, 26.3 mmol) in H2O (20.0 mL) was added dropwise at 15 °C. The resulting mixture was stirred at 25 °C for 12 hr. The reaction solution was added with saturated citric acid aqueous solution to adjust the pH to 4 and diluted with H2O 100 mL, and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with H2O (100 mL * 3) and brine (100 mL * 2) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by re-crystallization from hexane and EtOAc (100 mL, 1:4) at 25 °C for 3 hrs to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(l,3,4-thiadiazol-2-yl)propanoic acid (2.24 g, 4.00 mmol, 60.8% yield). MS ESI calculated for C3oH3iN307[M+H]+546.22, found 546.2.

[2662] Scheme 10. Synthesis of (2S)-3-(3-ethylimidazol-4-yl)-2-(9H-fluoren-9-

[2663]

[2664]

[0377] Step 1: To a solution of (2S)-2-(9H-fluoren-9-yhnethoxycarbonylamino)-3-(l-tritylimidazol-4-yl)propanoic acid (10.0 g, 16.1 mmol) and HOBt (2.18 g, 16.1 mmol) in THF (100 mL) slowly dropwise added DCC (3.32 g, 16.1 mmol) in THF (70.0 mL) and MeOH (70.0 mL) at -10 °C under N2 atmosphere. The mixture was stirred at 25 °C for 20 hrs. The mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC to afford methyl (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(l-tritylimidazol-4-yl)propanoate (9.88 g, 15.4 mmol, 95.6% yield). MS ESI calculated for C41H35N3O4 [M+H]+634.26, found 634.2.

[2665]

[0378] Step 2: To a solution of methyl (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(l-tritylimidazol-4-yl)propanoate (6.00 g, 9.46 mmol) in DMF (30.0 mL) was added iodoethane (7.38 g, 47.3 mmol, 3.78 mL) at 0 °C. The mixture was stirred at 25 °C for 18 hrs. The mixture was added iodoethane (2.27 mL, 28.4 mmol) and stirred at 25 °C for 15 hrs. The reaction mixture was diluted with DCM 120 mL and washed with saturated NaHCO; aqueous solution 140 mL (70 mL * 2), water 90 mL (30 mL * 3) and brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl (2S)-3-(3-ethyl-l-trityl-imidazol-3-ium-4-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoate (6.27 g, crude). MS ESI calculated for C43FLoN304+[M+H]+662.30, found 662.5.

[2666]

[0379] Step 3: To a solution of methyl (2S)-3-(3-ethyl-l-trityl-imidazol-3-ium-4-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoate (6.27 g, 9.46 mmol) in DCM (62.0 mL) was added TFA (31 mL, 418 mmol) and triisopropylsilane (2.13 mL, 10.4 mmol). The mixture was stirred at 25 °C for 3 hrs. The reaction mixture was diluted with water 200 mL and hexane 100 mL. Brown oily substances precipitated from the reaction solution. The mixture was filtered. The filtrate was extracted with hexane 150 mL (50 mL * 3). The aqueous phase and brown oily substances produced by freeze-drying to afford methyl (2S)-3-(3-ethylimidazol-4-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoate (5.04 g, crude). MS ESI calculated for C24H25N3O4 [M+H]+420.18, found 420.2.

[2667]

[0380] Step 4: To a solution of methyl (2S)-3-(3-ethylimidazol-4-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoate (5.04 g, 9.44 mmol) in dioxane (50.0 mL) was added 6 M HC1 aqueous solution (50.0 mL). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove dioxane (50.0 mL). The mixture was produced by freeze-drying to afford the residue. The residue was purified by prep-HPLC (0.05%HCl condition) to afford (2S)-3-(3-ethylimidazol-4-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (1.00 g, 2.20 mmol, 23.3% yield). MS ESI calculated for C23H23N3O4 [M+H]+406.17, found 406.3.

[2668] Scheme 11. Synthesis of (2S)-3-[4-(tert-butoxycarbonylamino)-3-pyridyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid

[2669] Step 1 Step 2

[2670] o

[2671] Zn PdCI2, Xphos DMF NHFmoc DMF

[2672] Step 3

[2673] LiOH»H2O, CaCI2

[2674] THF, H2O, i-PrOH

[2675]

[2676]

[0381] Step 1: To a solution of Zn (28.9 g, 443 mmol) in DMF (20 mL) was added methyl (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-iodo-propanoate (40.0 g, 88.6 mmol) in DMF (180 mL) under N2. The mixture was stirred at 25 °C for 2 hrs. The crude product [(2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc as DMF solution was used into the next step without further purification.[2677...

Claims

CLAIMSWhat is claimed is:

1. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(REF ID NO: 1), wherein:X1is aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement;X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via an X3-X13crosslink;X4and X10are crosslinked amino acids connected via an X4-X10crosslink;X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or is absent;X6is a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile); andX11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; andX12is proline (P), D-proline (D-Pro), or a proline replacement.

2. The cyclic peptide of claim 1, or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide comprises the amino acid sequence:X1-X2-Pen*-X4-G-X6-X7-X8-X9-X10-Y-P-C* (REF ID NO: 2), wherein Pen is penicillamine and * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink.

3. The cyclic peptide of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1is a lysine replacement.

4. The cyclic peptide of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, RNRN^N7R1RNR3J. OHH2N Ywherein X1is a lysine replacement of Formula (h-2): O (h-2), or a D-isomer thereof, wherein:m is 1, 2, 3, or 4;each R1is independently hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl;R3is hydrogen or Ci-6 alkyl;each instance of RNis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -C(=O)RB, -S(=O)2RB, C3-8 carbocyclyl, Cg-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl, or two RNattached to the same nitrogen atom are joined together to form 3-8 membered heterocyclyl; andeach RBis independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 carbocyclyl, Ce-io aryl, 3-8 membered heterocyclyl, or 5-10 membered heteroaryl.

5. The cyclic peptide of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X2is phenylalanine (F).

6. The cyclic peptide of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein X4is glutamic acid (E), lysine (K), or a lysine replacement; X10is N-methyl-glutamic acid (NMeE) or is N-methyl-lysine (NMeK); and X4and X10are crosslinked to formO or O, wherein each a represents the point of attachment to the a-carbon of X4or X107. The cyclic peptide of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein X6is a histidine replacement.

8. The cyclic peptide of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X7is phenylalanine.

9. The cyclic peptide of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X8is glycine (G).

10. The cyclic peptide of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X9is a sarcosine replacement.

11. The cyclic peptide of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein the C-terminus of the cyclic peptide is amidated (-NH2).

12. A dimer, or a pharmaceutically acceptable salt thereof, comprising two cyclic peptides, wherein:the two cyclic peptides are independently cyclic peptides of any one of claims 1-11; and the two cyclic peptides are conjugated to each other via a bond or a linker.

13. The dimer of claim 12, wherein the two cyclic peptides are the same.

14. The dimer of claim 12 or 13, wherein the two cyclic peptides are conjugated to each other via the N-terminus of each cyclic peptide.

15. The dimer of any one of claims 12-14, or a pharmaceutically acceptable salt thereof, wherein the linker comprises Ci- 10 alkylene.

16. The cyclic peptide or dimer of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein the dimer further comprises a lipid group.

17. The cyclic peptide or dimer of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein the lipid group comprises one or more of the following in any combination:, wherein nl is 1, 2, 3, or 4;OH, wherein pl is an integer from 1-30, inclusive.

18. The cyclic peptide or dimer of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein the lipid group comprises:wherein n2 is 0, 1, 2, 3, or 4.

19. The dimer of any one of claims 12-18, or a pharmaceutically acceptable salt thereof, wherein the lipid group is attached to the linker conjugating the two cyclic peptides.

20. The dimer of any one of claims 12-19, or a pharmaceutically acceptable salt thereof, wherein the linker comprises:

21. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(REF ID NO: 1), wherein:X1is arginine (R), D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), a cysteine replacement, or other amino acid, wherein X3and X13are crosslinked amino acids connected via an X3-X13crosslink;X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), D-glutamic acid (D-Glu), or other amino acid;X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid, or is absent;X6is histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A),D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid;X10is N-methyl-leucine (NMeL), D-N-methyl-leucine (D-NMeL), N-methyl-aspartic acid (NMeD), D-N-methyl-aspartic acid (D-NMeD), N-methyl-glutamic acid (NMeE), D-N-methyl-glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), N-methyl-lysine (NMeK), D-N-methyl-lysine (D-NMeK), lysine (K), D-lysine (D-Lys), or other amino acid;X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; andX12is proline (P), D-proline (D-Pro), or a proline replacement;optionally wherein:X1and X13are crosslinked amino acids connected via an X’-X13crosslink; and / orX4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink;provided that:X1is not R and is not absent; and / orX2is not F; and / orX3is not Pen; and / orX5is not G; and / orX9is not Sar; and / orX10is not NMeL; and / orX13is not C; and / orX1and X13are crosslinked amino acids connected via a X’-X13crosslink; and / orX4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

22. The cyclic peptide of claim 21, or a pharmaceutically acceptable salt thereof, wherein:X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent;X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;X3and X13are each independently penicillamine (Pen), D-penicillamine (D-Pen), cysteine (C), D-cysteine (D-Cys), or a cysteine replacement;X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;X5is glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile), or is absent;X6is histidine (H), D-histidine (D-His), or a histidine replacement;X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);X10is N-methyl-leucine (NMeL), D-N-methyl-leucine (D-NMeL), N-methyl-aspartic acid (NMeD), D-N-methyl-aspartic acid (D-NMeD), N-methyl-glutamic acid (NMeE), or D-N-methyl-glutamic acid (D-NMeE);X11is tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, phenylalanine (F), D-phenylalanine (D-Phe), or a phenylalanine replacement; andX12is proline (P), D-proline (D-Pro), or a proline replacement.

23. The cyclic peptide of claim 21 or 22, or a pharmaceutically acceptable salt thereof, wherein:X1is arginine (R), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent;X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;X3and X13are each independently penicillamine (Pen), cysteine (C), or a cysteine replacement; X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement;X5is glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I), or is absent;X6is histidine (H) or a histidine replacement;X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I);X10is N-methyl-leucine (NMeL), N-methyl-aspartic acid (NMeD), or N-methyl-glutamic acid (NMeE);X11is tyrosine (Y), a tyrosine replacement, phenylalanine (F), or a phenylalanine replacement; andX12is proline (P) or a proline replacement.

24. The cyclic peptide of any one of claims 21-23, or a pharmaceutically acceptable salt thereof, wherein X3is Pen.

25. The cyclic peptide of any one of claims 21-24, or a pharmaceutically acceptable salt thereof, wherein X5is G.

26. The cyclic peptide of any one of claims 21-25, or a pharmaceutically acceptable salt thereof, wherein X8is G or Sar.

27. The cyclic peptide of any one of claims 21-26, or a pharmaceutically acceptable salt thereof, wherein X11is Y.

28. The cyclic peptide of any one of claims 21-27, or a pharmaceutically acceptable salt thereof, wherein X12is P.

29. The cyclic peptide of any one of claims 21-28, or a pharmaceutically acceptable salt thereof, wherein X13is C.

30. The cyclic peptide of any one of claims 21-29, or a pharmaceutically acceptable salt thereof, wherein a-sidechains of X3and X13are connected to form the X3-X13crosslink.

31. The cyclic peptide of any one of claims 21 -30, or a pharmaceutically acceptable salt thereof, wherein the X3-X13crosslink connects the a-carbons of X3and X13.

32. The cyclic peptide of any one of claims 21-31, or a pharmaceutically acceptable salt thereof, wherein the X3-X13crosslink is a bond, C1-10alkylene, C1-10haloalkylene, C1-10heteroalkylene, C1-10alkenylene, C1-10heteroalkenylene, C1-10alkynylene, C1-10heteroalkynylene, C3-8carbocyclylene, C6-10arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

33. The cyclic peptide of any one of claims 21-32, or a pharmaceutically acceptable salt thereof,a awherein the X3-X13crosslink is' ' or / ', wherein each a represents the point of attachment to the a-carbon of X3or X13.

34. A cyclic peptide, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence:X1-X2-Pen*-X4-G-X6-X7-X8-X9-X10-Y-P-C* (REF ID NO: 2),wherein:Pen is penicillamine and * denotes crosslinked amino acids connected to each other via a Pen*-C* crosslink;X1is arginine (R), D-arginine (D-Arg), aspartic acid (D), D-aspartic acid (D-Asp), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), a lysine replacement, or other amino acid, or is absent;X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), a lysine replacement, aspartic acid (D), D-aspartic acid (D-Asp), glutamic acid (E), D-glutamic acid (D-Glu), or other amino acid;X6is histidine (H), D-histidine (D-His), a histidine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), a tyrosine replacement, or other amino acid, or is absent;X8is glycine (G), a glycine replacement, sarcosine (Sar), a sarcosine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), D-isoleucine (D-Ile), or other amino acid; andX10is -methyl-leucine (NMeL), D--methyl-leucine (D-NMeL), -methyl-aspartic acid (NMeD), D--methyl-aspartic acid (D-NMeD), -methyl-glutamic acid (NMeE), D--methyl-glutamic acid (D-NMeE), glutamic acid (E), D-glutamic acid (D-Glu), -methyl-lysine (NMeK), D--methyl-lysine (D-NMeK), lysine (K), D-lysine (D-Lys), or other amino acid;optionally wherein:X1and C* are crosslinked amino acids connected via an X’-C* crosslink; and / orX4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10are crosslinked amino acids connected via an X4-X10crosslink;provided that:X1is not R and is not absent; and / orX2is not F; and / orX9is not Sar; and / orX10is not NMeL; and / orX1and C* are crosslinked amino acids connected via an X’-C* crosslink; and / orX4and X9are crosslinked amino acids connected via an X4-X9crosslink, or X4and X10arecrosslinked amino acids connected via an X4-X10crosslink.

35. The cyclic peptide of claim 34, or a pharmaceutically acceptable salt thereof, wherein:X1is arginine (R), D-arginine (D-Arg), asparagine (N), D-asparagine (D-Asn), glutamine (Q), D-glutamine (D-Gln), leucine (L), D-leucine (D-Leu), lysine (K), D-lysine (Lys), or a lysine replacement, or is absent;X2is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;X4is threonine (T), D-threonine (D-Thr), a threonine replacement, serine (S), D-serine (D-Ser), a serine replacement, lysine (K), D-lysine (Lys), or a lysine replacement;X6is histidine (H), D-histidine (D-His), or a histidine replacement;X7is phenylalanine (F), D-phenylalanine (D-Phe), a phenylalanine replacement, tyrosine (Y), D-tyrosine (D-Tyr), or a tyrosine replacement, or is absent;X8is glycine (G) or sarcosine (Sar);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), D-alanine (D-Ala), valine (V), D-valine (D-Val), leucine (L), D-leucine (D-Leu), isoleucine (I), or D-isoleucine (D-Ile); andX10is -methyl-leucine (NMeL), D--methyl-leucine (D-NMeL), -methyl-aspartic acid (NMeD), D--methyl-aspartic acid (D-NMeD), -methyl-glutamic acid (NMeE), or D--methyl-glutamic acid (D-NMeE).

36. The cyclic peptide of claim 34 or 35, or a pharmaceutically acceptable salt thereof, wherein:X1is arginine (R), asparagine (N), glutamine (Q), leucine (L), lysine (K), or a lysine replacement, or is absent;X2is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;X4is threonine (T), a threonine replacement, serine (S), a serine replacement, lysine (K), or a lysine replacement;X6is histidine (H) or a histidine replacement;X7is phenylalanine (F), a phenylalanine replacement, tyrosine (Y), or a tyrosine replacement, or is absent;X8is glycine (G) or sarcosine (Sar);X9is sarcosine (Sar), a sarcosine replacement, glycine (G), a glycine replacement, alanine (A), valine (V), leucine (L), or isoleucine (I); andX10is -methyl-leucine (NMeL), -methyl-aspartic acid (NMeD), or -methyl-glutamic acid (NMeE).

37. The cyclic peptide of any one of claims 34-36, or a pharmaceutically acceptable salt thereof,wherein a-sidechains of Pen* and C* are connected to form the Pen*-C* crosslink.

38. The cyclic peptide of any one of claims 34-37, or a pharmaceutically acceptable salt thereof, wherein the Pen*-C* crosslink connects the a-carbons of Pen* and C*.

39. The cyclic peptide of any one of claims 34-38, or a pharmaceutically acceptable salt thereof, wherein the Pen*-C* crosslink is a bond, C1-10alkylene, C1-10haloalkylene, C1-10heteroalkylene, C1-10alkenylene, C1-10heteroalkenylene, C1-10alkynylene, C1-10heteroalkynylene, C3-8carbocyclylene, C6-10arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

40. The cyclic peptide of any one of claims 34-39, or a pharmaceutically acceptable salt thereof,wherein the Pen*-C* crosslink iswherein each a represents the point of attachment to the a-carbon of Pen* or C*.

41. The cyclic peptide of any one of claims 21 -40, or a pharmaceutically acceptable salt thereof, wherein X1is R, N, or L, or is absent.

42. The cyclic peptide of any one of claims 21-40, or a pharmaceutically acceptable salt thereof,wherein X1is K, or a lysine replacement selected from:

43. The cyclic peptide of any one of claims 21-33, 41, and 42, or a pharmaceutically acceptable salt thereof, wherein X1and X13are crosslinked amino acids connected via an X’-X13crosslink.

44. The cyclic peptide of any one of claims 21-33 and 41-43, or a pharmaceutically acceptable salt thereof, wherein the a-sidechain of X1and the C-terminus of X13are connected to form the X’-X13crosslink.

45. The cyclic peptide of any one of claims 21-33 and 41-44, or a pharmaceutically acceptable salt thereof, wherein the X’-X13crosslink connects the a-carbon of X1and the C-terminus of X13.

46. The cyclic peptide of any one of claims 21-33 and 41-45, or a pharmaceutically acceptable salt thereof, wherein the X’-X13crosslink is a bond, C1-10alkylene, C1-10haloalkylene, C1-10heteroalkylene, C1-10alkenylene, C1-10heteroalkenylene, C1-10alkynylene, C1-10heteroalkynylene, C3-8carbocyclylene, C6-10 arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

47. The cyclic peptide of any one of claims 21-33 and 41-46, or a pharmaceutically acceptable saltthereof, wherein the X'-X13crosslink is O, wherein each a represents the point of attachment to the a-carbon of X1or X13.

48. The cyclic peptide of any one of claims 34-42, or a pharmaceutically acceptable salt thereof, wherein X1and C* are crosslinked amino acids connected via an X’-C* crosslink.

49. The cyclic peptide of any one of claims 34-42 and 48, or a pharmaceutically acceptable salt thereof, wherein the a-sidechain of X1and the C-terminus of C* are connected to form the X’-C* crosslink.

50. The cyclic peptide of any one of claims 34-42, 48, and 49, or a pharmaceutically acceptable salt thereof, wherein the X’-C* crosslink connects the a-carbon of X1and the C-terminus of C*.

51. The cyclic peptide of any one of claims 34-42 and 48-50, or a pharmaceutically acceptable salt thereof, wherein the X’-C* crosslink is a bond, C1-10alkylene, C1-10haloalkylene, C1-10heteroalkylene, C1-10alkenylene, C1-10heteroalkenylene, C1-10alkynylene, C1-10heteroalkynylene, C3-8carbocyclylene, C6-10 arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

52. The cyclic peptide of any one of claims 34-42 and 48-50, or a pharmaceutically acceptable saltthereof, wherein the X’-C* crosslink is O, wherein each a represents the point ofattachment to the a-carbon of X1or C*.

53. The cyclic peptide of any one of claims 21-52, or a pharmaceutically acceptable salt thereof,wherein X2is F, a phenylalanine replacement selected from:is absent.

54. The cyclic peptide of any one of claims 21-53, or a pharmaceutically acceptable salt thereof,55. The cyclic peptide of any one of claims 21-54, or a pharmaceutically acceptable salt thereof, wherein X6is H.

56. The cyclic peptide of any one of claims 21-54, or a pharmaceutically acceptable salt thereof,wherein X6is a histidine replacement selected from:0 0 0 0N-NHH70 A Ax A, N A<0HH A<OHH IA<0HHNVH / ° H NV. OH H2N IT rl2^ H H2N if H2N T[ H2N n o o o o b o 0 0 0 0 o o 0 0 0Cl xs XX, Ys A ° x H r^NNA T< T0HH H2NNA |T<0HH H2NNA T<f0HH H2NNA |T<0HH H2IN? V |jOH0 0 o o oor is a lysine replacement selected from:

57. The cyclic peptide of any one of claims 21-56, or a pharmaceutically acceptable salt thereof, wherein X7is F.

58. The cyclic peptide of any one of claims 21-56, or a pharmaceutically acceptable salt thereof,59. The cyclic peptide of any one of claims 21-58, or a pharmaceutically acceptable salt thereof, wherein X9is Sar.

60. The cyclic peptide of any one of claims 21-58, or a pharmaceutically acceptable salt thereof,wherein X9is a sarcosine replacement selected from:OH OH OH OH OH OH61. The cyclic peptide of any one of claims 21 -60, or a pharmaceutically acceptable salt thereof, wherein X4and X9are crosslinked amino acids connected via an X4-X9crosslink.

62. The cyclic peptide of any one of claims 21-61, or a pharmaceutically acceptable salt thereof, wherein the a-sidechain of X4and the a-amino group of X9are connected to form the X4-X9crosslink.

63. The cyclic peptide of any one of claims 21-62, or a pharmaceutically acceptable salt thereof, wherein the X4-X9crosslink connects the a-carbon of X4and the a-amino group of X9.

64. The cyclic peptide of any one of claims 21-63, or a pharmaceutically acceptable salt thereof, wherein the X4-X9crosslink is a bond, C1-10 alkylene, C1-10 haloalkylene, C1-10 heteroalkylene, C1-10 alkenylene, C1-10 heteroalkenylene, C1-10 alkynylene, C1-10 heteroalkynylene, C3-8 carbocyclylene, C6-10 arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

65. The cyclic peptide of any one of claims 21-64, or a pharmaceutically acceptable salt thereof,wherein the X4-X9crosslink isO of attachment to the a-carbon of X4, and the • represents the point of attachment to the a-amino group of66. The cyclic peptide of any one of claims 21-65, or a pharmaceutically acceptable salt thereof, wherein X10is NMeL.

67. The cyclic peptide of any one of claims 21-65, or a pharmaceutically acceptable salt thereof, wherein X10is NMeD or NMeE.

68. The cyclic peptide of any one of claims 21-67, or a pharmaceutically acceptable salt thereof, wherein X4and X10are crosslinked amino acids connected via an X4-X10crosslink.

69. The cyclic peptide of any one of claims 21-68, or a pharmaceutically acceptable salt thereof, wherein a-sidechains of X4and X10are connected to form the X4-X10crosslink.

70. The cyclic peptide of any one of claims 21-69, or a pharmaceutically acceptable salt thereof, wherein the X4-X10crosslink connects the a-carbons of X4and X10.

71. The cyclic peptide of any one of claims 21 -70, or a pharmaceutically acceptable salt thereof, wherein the X4-X10crosslink is a bond, C1-10 alkylene, C1-10 haloalkylene, C1-10 heteroalkylene, C1-10 alkenylene, C1-10 heteroalkenylene, C1-10 alkynylene, C1-10 heteroalkynylene, C3-8 carbocyclylene, C6-10 arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

72. The cyclic peptide of any one of claims 21-71, or a pharmaceutically acceptable salt thereof,wherein the X4-X10crosslink isOHz N. / a \ J] / aor O, wherein each a represents the point of attachment to the a-carbon of X4or X10.

73. The cyclic peptide of any one of claims 21-33 or 41-72, or a pharmaceutically acceptable saltthereof, wherein X11is a tyrosine replacement selected from:O, OO, and O74. The cyclic peptide of any one of claims 21-33 or 41-73, or a pharmaceutically acceptable saltthereof, wherein X12is a proline replacement selected from:

75. The cyclic peptide of any one of claims 21-74, or a pharmaceutically acceptable salt thereof, wherein the N-terminus of the cyclic peptide is acylated.

76. The cyclic peptide of any one of claims 21-75, or a pharmaceutically acceptable salt thereof, wherein the C-terminus of the cyclic peptide is amidated (-NH2or -NH-).

77. The cyclic peptide of any one of claims 21-76, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence of any one of REF ID NOs: 3-985.

78. The cyclic peptide of any one of claims 21-77, or a pharmaceutically acceptable salt thereof, wherein the cyclic peptide is selected from those in Table 2A, and pharmaceutically acceptable salts thereof.

79. The cyclic peptide of any one of claims 21-78, as a free base.

80. A dimer, or pharmaceutically acceptable salt thereof, comprising two cyclic peptides, wherein:the two cyclic peptides are independently cyclic peptides of any one of claims 21-79; and the two cyclic peptides are conjugated to each other via a bond or a linker.

81. The dimer of claim 80, or a pharmaceutically acceptable salt thereof, wherein, for at least one of the cyclic peptides, the linker is attached at:X1ofREF ID NO: 1;X2of REF ID NO: 1, wherein X1of REF ID NO: 1 is absent;X3of REF ID NO: 1, wherein X1and X2of REF ID NO: 1 are absent;X1of REF ID NO: 2;X2of REF ID NO: 2, wherein X1of REF ID NO: 2 is absent; orPen* of REF ID NO: 2, wherein X1and X2of REF ID NO: 2 are absent.

82. The dimer of claim 80 or 81, or a pharmaceutically acceptable salt thereof, wherein the linker is a bond, C1-10 alkylene, C1-10 haloalkylene, C1-10 heteroalkylene, C1-10 alkenylene, C1-10 heteroalkenylene, C1-10 alkynylene, C1-10 heteroalkynylene, C3-8 carbocyclylene, C6-10 arylene, 3-8 membered heterocyclylene, 5-10 membered heteroarylene, or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted.

83. The dimer of any one of claims 80-82, wherein the linker is selected from:594O84. The dimer of any one of claims 80-83, or a pharmaceutically acceptable salt thereof, wherein the dimer is selected from those in Table 2B, and pharmaceutically acceptable salts thereof.

85. A pharmaceutical composition comprising a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

86. A method of treating a neonatal fragment crystallizable receptor (FcRn) -mediated disease in asubject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

87. A method of treating an immunoglobulin G (IgG)-mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

88. A method of treating an autoimmune disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

89. A method of inhibiting FcRn in vitro or in vivo, comprising contacting an FcRn protein with a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

90. A method of decreasing IgG levels in a subject in need thereof comprising administering to the subject an effective amount of a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

91. A cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in:(a) treating a FcRn-mediated disease in a subject;(b) treating an IgG-mediated disease in a subject;(c) treating an autoimmune disease in a subject;(d) non-covalently inhibiting an FcRn activity in vitro or in vivo,' and / or(e) decreasing IgG levels in a subject.

92. Use of a cyclic peptide of any one of claims 21-79 or a dimer of any one of claims 80-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament.