Phosphorodiamidate morpholino oligomer conjugate compounds and their use in treating myotonic dystrophy type 1

Abstract

Delivery construct-oligonucleotide conjugates, pharmaceutical compositions, and their use for the treatment of myotonic dystrophy type 1 in a human subject are disclosed.

Description

PHOSPHORODIAMIDATE MORPHOLINO OLIGOMER CONJUGATE COMPOUNDS AND THEIR USE IN TREATING MYOTONIC DYSTROPHY TYPE 1CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application Number 63 / 736,971, filed December 20, 2024; U. S. Provisional Patent Application Number 63 / 758,796, filed February 14, 2025; U. S. Provisional Patent Application Number 63 / 779,922 filed March 28, 2025; and U. S. Provisional Patent Application Number 63 / 859,555 filed August 7, 2025, each of which is incorporated herein by reference in its entirety.SEQUENCE LISTING

[0002] This application contains a Sequence Listing electronically submitted via Patent Center to the United States Patent and Trademark Office as an.xml file entitled“0755__000113WO01_ST26.xml” having a size of 143.411 bytes and created on December 18, 2025. The information contained in the Sequence Listing is incorporated by reference herein.FIELD

[0003] The present disclosure relates to compounds, compositions, and methods that can be used to treat myotonic dystrophy type 1. The compounds include a cargo that targets the expanded CUG repeat in heDMPK transcript associated with myotonic dystrophy type 1.BACKGROUND

[0004] Myotonic dystrophy type 1 (DM1) is a serious, progressive, disabling genetic disease that leads to early death in many patients. DM1 is inherited in an autosomal dominant manner and is characterized by progressive muscle weakness, myotonia (delayed muscle relaxation after contraction), and other systemic manifestations. DM1 affects at least 1 in 10,000 people worldwide or approximately 110,000 people in the United States and Europe (see Ashizawa T, Gagnon C, Groh WJ, Gutmann L, Johnson NE, Meola G, et al. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018;8(6):507-20; Myotonic Dystrophy Foundation. Myotonic Dystrophy Clinical Research Network.Available at: myotonic.org / myotonic-dystrophy-clinical-research-network; and Johnson NE, Butterfield RJ, Mayne K, Newcomb T, Imburgia C, Dunn D, et al. Population-based prevalenceof myotonic dystrophy type 1 using genetic analysis of statewide blood screening program. Neurology. 2021;96(7):e1045-53)..

[0005] The clinical presentation of DM1 varies considerably among patients with the disease, but in nearly all cases, multiple systems throughout the body are affected. Muscular weakness and myotonia are the cardinal clinical symptoms of DM1. Fatigue is among the most impactful symptoms of DM1, due to the combination of muscle weakness, respiratory failure, sleep disordered breathing, and excessive daytime sleepiness (see Heatwole C, Bode R, Johnson N, Quinn C, Martens W, McDermott MP, et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology. 2012;79(4):348-57; and Johnson NE Myotonic Muscular Dystrophies. Continuum (Minneap Minn). 2019;25(6): 1682-95). Symptom onset is typically in the third decade of life, with progressive weakness leading to approximately 50% of patients being wheelchair bound by time of death (see Turner C, Hilton-Jones D. Myotonic dystrophy: diagnosis, management and new therapies. Curr Opin Neurol. 2014;27(5):599-606; and de Die-Smulders CE, Howeler CJ, Thijs C, Mirandolle JF, Anten HB, Smeets HJ, et al. Age and causes of death in adult-onset myotonic dystrophy. Brain. 1998;121 (Pt 8):1557-63.) The average age of death in non-congenital forms of DM1 is 54 years of age, with 70% of early mortality caused by cardio-respiratory complications.

[0006] The underlying molecular cause of DM1 is an expanded CTG repeat sequence in the 3' untranslated region in one allele of the DM1 Protein Kinase (DMPK) gene. The CTG trinucleotide repeat is transcribed into an RNA containing a toxic CUG repeat, where it forms "hairpins" that sequester multiple proteins involved in splicing of various downstream transcripts into “nuclear foci”, including muscleblind-like protein 1 (MBNL1). The resulting systemic missplicing leads to downstream consequences in many cell types including muscle.

[0007] Currently, there is no cure for DM1 and no US Federal and Drug Administration approved treatments exist that target the cause of DM 1, the expanded CTG CUG. Treatments focus on managing the symptoms of DM1 manifested on a patient basis.

[0008] Biologic macromolecules, such as oligonucleotides, hold enormous potential as therapeutic agents, for example, to treat DM1. However, a challenge in bringing biologic macromolecule therapies to the clinic is their limited ability to access the intracellular compartment when administered systemically. As such there is a need for effective DM1 treatments, such as, for example, biological macromolecule treatments.SUMMARY

[0009] The present disclosure relates to compound, compositions, and methods that can be used to treat myotonic dystrophy. The compounds include a delivery construct conjugated to a cargo. The delivery construct comprises a cyclic cell penetrating peptide (cCPP) and one or more exocyclic amino acids and / or peptides. The cargo comprises an oligonucleotide that targets the expanded CUG repeat in the DMPK transcript associated with myotonic dystrophy.

[0010] In embodiments, the compound is of Formula III:R28~(AA1^ — N (M’)™ cargo mlor a pharmaceutically acceptable salt thereof,where:OR20isH or ''a1, a2, a3, and a4 are each independently 0 or 1, where at least one of a2, a3, and a4 is 1;wl, w2, and w3 are each independently 0 or 1, where at least one of w2 and w3 is 1AA1 is an amino acid residue or a peptide that comprises 2 to 10 amino acid residues;AA2, AA3, and AA4 are each independently an amino acid residue or a peptide that comprises 1 to 6 amino acids residues, where at least one of AA2, AA3, and AA4 is present in the compound and comprises a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;j1, j1, and j2 are each independently an integer from 1 to 4;xl, x2, and x3 are each independently an integer from 1 to 14,n is an integer from 0 to 3;y is an integer from 1 to 5;ml is 0 or 1;OM' comprises -NH-,', or a heteroaryl wherein t is an integer from 0 to 10;R1, R2, R3, R4, R5, R6, and R7are each independently the side chain an amino acid residue; andcargo comprises an oligonucleotide comprising the sequence:5'-CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG-3' (SEQ ID NO: 74),5'-CAG CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 73), 5'-CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 72),5'-CAG CAG CAG CAG CAG CAG CAG -3'(SEQ ID NO: 71), 5'-CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 70),5' -CAG CAG CAG CAG CAG -3' (SEQ ID NO: 69),5'-CAG CAG CAG CAG -3'(SEQ ID NO: 68),5'-CAG CAG CAG -3, or5'-CAG CAG -3'.

[0011] In embodiments, the compound is of Formula A, Formula B, Formula C, Formula D, Formula F:Formula A:H I / (lyi’HcargoFormula B:s O O JL.^k,.oL JL-^J Jx'xJik ^(irhw p- oPr PY N \ - ZM (AA3^ V ° / ¥ A Y / x A ® f <k M. H »2 $2 USJj 0l? *“ -’w >? W; H £M f 0 0 y..< < / “H 0. R4.n8-H yR* HH H* / 1*0OA_, MH I / " R3n\ / / / 1SK 0Formula C:HLHo?, 9 4 4 / o 4H' *3'o | U 9O • H 0.^' k <, Q 0, } _ R1AO^H 4''-^ ” HH'0** >. ■( / 0 Formula D:Formula E:or a pharmaceutically acceptable salt thereof wherein the variables are described herein.

[0012] In embodiments, the oligonucleotide cargo is a PMO.BRIEF DESCRIPTION OF THE FIGURES

[0013] FIG. 1 shows modified nucleosides and nucleotides that can be used in antisense oligonucleotides described herein. Structures 1-3 (1 = phosphorothioate; 2 = (Scs-Rp)-a, P-CAN; 3 = phosphorodiamidate morpholino (PMO)) are dinucleotides showing phosphate backbone and / or sugar modifications; 4 (2-thio-dT) is a base modification; 5-8 (5 = 2 -OMe-RNA; 6 = 2'O-MOE-RNA; 7 = 2'F-RNA; 8 = 2'F-ANA) are 2' sugar modifications; 9-11 are constrained nucleotides; 12-14 (9 = LNA; 10 = (S)-cET; 11 = tcDNA; 12 = FHNA; 13 = (S)5'-C-methyl; 14 = UNA) are additional sugar modification; and 15-18 (15= E-VP 16 = methyl phosphonate; 17 = 5' phosphorothioate; 18 = (S)-5'-C-methyl with phosphate) are 5' phosphate stabilization modifications; 19 is a morpholino sugar. Reformatted from Khvorova, A., et al., Nat. Biotechnol.2017 Mar; 35(3): 238-248.

[0014] FIG. 2 shows a methylenemorpholine sugar (structure 1) and a three nucleotide phosphorodiamidate morpholino oligomer (structure 2).

[0015] FIG. 3 shows a peptide nucleic acid (PNA).

[0016] FIGS. 4A-4MM show the structures of compound number 24 (FIG. 4A), compound number 25 (FIG. 4B), compound number 27 (FIG. 4C), compound number 28 (FIG. 4D), compound number 29 (FIG. 4E), compound number 31 (FIG. 4F), compound number 32 (FIG.4G), compound number 54 (FIG. 4H), compound number 55 (FIG. 4I), compound number 56 (FIG. 4J), compound number 57 (FIG. 4K), compound number 65 (FIG. 4L), compound number 67 (FIG. 4M), compound number 71 (FIG. 4N), compound number 73 (FIG. 4O), compound number 74 (FIG. 4P), compound number 75 (FIG. 4Q), compound number 77 (FIG.4R), compound number 82 (FIG. 4S), compound number 89 (FIG. 4T), compound number 95 (FIG. 4U), compound number 89 (FIG. 4V), compound number 104 (FIG. 4W), compound number 105 (FIG. 4X), compound number 106 (FIG. 4Y), compound number 86 (FIG. 4Z), compound number 101 (FIG. 4AA), compound number 100 (FIG. 4BB), compound number 120 (FIG. 4CC), compound number 92 (FIG. 4DD), compound number 96 (FIG. 4EE), compound number 115 (FIG. 4FF), compound number 76 (FIG. 4GG), compound number 64 (FIG.4HH), compound number 63 (FIG. 4II), compound number 78 (FIG. 4J J), compound number 60 (FIG. 4KK), compound number 59 (FIG. 4LL), and compound number 68 (FIG. 4MM). RPMOis shown in FIG. 5.

[0017] FIG. 5 shows the structure of R™°.

[0018] FIGS. 6A-6C show synthetic schemes for synthesizing Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-[CAG]7. Synthesis includes resin loading and sequence elongation (FIG. 6A), deallylation and cyclization (FIG. 6B), and conjugation of the EEV with the PMO (FIG. 6C).DETAILED DESCRIPTION

[0019] The present disclosure describes compounds, compositions containing the compounds, and methods of administration of the compositions. The compounds and compositions can be administered to a patient to treat DM1.

[0020] The compounds are cargo conjugates that include a cargo and a delivery construct.Generally, the cargo is the effector moitey that elicits a response. For example, the cargo can be a molecule that elicits a response effective for treating DM1. The delivery construct facilitates cell penetration and / or endosomal escape. The delivery construct can be referred to as an endosomal escape vehicle (EEV).

[0021] The underlying molecular cause of DM1 is an expanded CTG repeat sequence in the 3' untranslated region in one allele of the DM1 protein kinase (DMPK) gene. The CTG trinucleotide repeat is transcribed into an RNA containing a toxic CUG repeat. The CUG repeats bind various proteins involved in splicing, including muscleblind-like protein 1 (MBNL1).Protein-bound DMPK mRNA can aggregate in the nuclease to form nuclear foci. Due to the sequestration of splicing factors, the splicing of various genes is disrupted including MBLN1, CLCN1, AP2A1, RYR1, KIF13A, VSP39, NFIX, CLASP, BINI, and others. The resulting systemic mis-splicing leads to downstream consequences in many cell types including muscle.

[0022] The compounds of the present disclosure include a cargo desgined to target the underlying cause of DM1 The cargo comprises an oligonucleotide. The oligonculetodie can be an antisense oligonculeotide (ASO). The term ASO refers to an oligonucleotide sequence that is complementary, or at least partially complementary, to at least a portion of a target nucleotide sequence. A target nucleotide sequence is a part of a target transcript. In the present disclosure, the target nucleotide sequence comprises at least a portion of the CUG repeat of a DMPK transcript (a target transcript). The target nucleotide sequence can be a part of a DMPK pre-mRNA transcript, DMPK mRNA transcript, or both.

[0023] It is hypothesized that an ASO that hybridizes to at least a portion of the CUG repeat (i e., the target nucleotide sequence) of a DMPK transcript can sterically block proteins (e.g., MBNL1) from binding to the expanded CUG repeat regions. The free proteins are available to affect proper splicing of various downstream genes. Additionally, it is hypothesized that hybridization of an ASO to at least a portion of the CUG repeat of a DMPK transcript can prevent the formation of the DMPK transcript containing nuclear foci associated with the DM1 disease state. As such, in embodiments, hybridization of the ASO to a DMPK transcript, results in the rescue of mis-splicing of downstream genes / transcripts, thereby, reducing the level of downstream transcripts associated with the DM1 disease phenotype, increasing the level of downstream genes / transcripts associated with a healthy phenotype, or both.

[0024] The cargo comprises an ASO having a sequence that can hybrdize with at least a poriton of the CUG repeat region of a DMPK transcript. The number of nucleobases in an ASO can vary. In embodiments, the ASO is from 5 to 50 nucleobases in length, which can also be referred to as the length of the ASO. In embodiments, the ASO is 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or more, 40 or more, or 45 or more nucleobases in length. In embodiments, the ASO is 50 or less, 45 or less, 40 or less, 35 or less, 30 or less, 25 or less, 20 or less, 15 or less, or 10 or less nucleobases in length. In embodiments, the ASO is 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 15, or 5 to 10 nucleobases in length. In embodiments, the ASO is 10 to 50, 10 to 45, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 10 to 20, or 10 to 15 nucleobases in length. In embodiments, the ASO is 15 to 50, 15 to 45, 15 to 40, 15 to 35, 15 to 30, 15 to 25, or 15 to 20 nucleobases in length. In embodiments, the ASO is 20 to 50, 20 to 45, 20 to 40, 20 to 35, 20 to 30, or 20 to 25 nucleobases in length. In embodiments, the ASO is 25 to 50, 25 to 45, 25 to 40, 25 to 35, or 25 to 30 nucleobases in length. In embodiments, the ASO is 30 to 50, 30 to 45, 30 to 40, or 30 to 35 nucleobases in length. In embodiments, the ASO is 35 to 50, 35 to 45, or 35 to 40 nucleobases in length. In embodiments, the ASO is 40 to 50 or 40 to 45 nucleobases in length. In embodiments, the ASO is 45 to 50 nucleobases in length. In embodiments, the ASO is 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleobases in length.

[0025] In embodiments, the ASO is 20 to 25, 21 to 25, 22 to 25, 23 to 25, or 24 to 25 nucleobases in length. In embodiments, the Aso is 21 to 25 nucleobases in length. In embodiments, the ASO is 22 to 25 nucleobases in length In embodiments, the ASO is 23 to 25 nucleobases in length. Inembodiments, the ASO is 24 to 25 nucleobases in length. In embodiments, the ASO is 20 nucleobases in length. In embodiments, the ASO is 21 nucleobases in length. In embodiments, the ASO is 22 nucleobases in length. In embodiments, the Aso is 23 nucleobases in length. In embodiments, the ASO is 24 nucleobases in length. In embodiments, the ASO is 25 nucleobases in length.

[0026] In embodiments, the ASO has 100% complementarity to a target nucleotide sequence. In embodiments, the ASO does not have 100% complementarity to a target nucleotide sequence. As used herein, the term "percent complementarity" refers to the number of nucleobases (e.g., natural nucleobase or modified nucleobase) of an ASO that have nucleobase complementarity with a corresponding nucleobase of a target nucleotide sequence divided by the total length (number of nucleobases) of the ASO. One skilled in the art recognizes that the inclusion of mismatches is possible without eliminating the activity of the antisense compound.

[0027] In embodiments, incorporation of nucleotide affinity modifications allows for a greater number of mismatches compared to an unmodified compound. Similarly, certain oligonucleotide sequences may be more tolerant to mismatches than other oligonucleotide sequences. One of ordinary skill in the art is capable of determining an appropriate number of mismatches between an ASO and a target nucleotide sequence, such as by determining the thermal melting temperature (Tm). Tm or ATm can be calculated by techniques that are familiar to one of ordinary skill in the art. For example, techniques described in Freier et al. (Nucleic Acids Research, 1997, 25, 22: 4429-4443) allow one of ordinary skill in the art to evaluate nucleotide modifications for their ability to increase the melting temperature of an RNA: DN A duplex.

[0028] In embodiments, the ASO comprises one or more CAG repeats. The reverse of 5'-CAG-3' (3'-GAC-5') sequence has 100% complementarity and can hybridize with a 5'-CUG-3' sequence. In embodiments, the ASO comprises 1 to 50 CAG repeats. In embodiments, the CAG repeats are contiguous In embodiments, the CAG repeats are not contiguous. In embodiments, the ASO comprises a nucleotide sequence that has an incomplete CAG repeat at the 5' end, the 3' end, or both. For example, in embodiments, the ASO comprises a sequence such as AG(CAG)n, G(CAG)n, (CAG)nAG, or (CAG)nA where n is an integer from 1 to 50. In embodiments, the ASO comprises 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 20 or more, 30 or more, or 50 or more CAG repeats. In embodiments, the ASO comprises 50 or less, 40 or less, 30 or less, 20 or less, 10 or less, 9 orless, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less CAG repeats. In embodiments, the ASO comprises 2 to 50, 2 to 20, 2 to 10, 4 to 10, 5 to 10, 6 to 10, 6 to 9, 6 to 8, or 6 to 7 CAG repeats. In embodiment, the ASO comprises 3 to 10 CAG repeats. In embodiment, the ASO comprises 4 to 10 CAG repeats. In embodiments, the ASO comprises 5 to 9 CAG repeats. In embodiments, the ASO comprises 4 to 8 CAG repeats. In embodiments, the ASO comprises 5 to 7 ASO repeats. In embodiment, the Aso comprises 6 or 7 CAG repeats. In embodiments, the ASO comprises 7 or 8 CAG repeats. In embodiment, the ASO comprises 3 to 4 CAG repeats.

[0029] In embodiment, the ASO comprises the sequence:5'-CAG-CAG-CAG-3';5'-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 68);5'-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 69);5'-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 70);5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 71);5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 72);5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 73), or5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 74).

[0030] In embodiment, the ASO comprises the sequence:5'-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 69);5'-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 70);5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 71);5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 72); or5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 73).

[0031] In embodiment, the ASO comprises the sequence:5'-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 70);5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 71); or5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 72).

[0032] In embodiment, the ASO comprises the sequence:5'-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 70) or5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 71).

[0033] In embodiment, the ASO comprises the sequence:5 '-C AG-CAG-C AG-CAG-C AG-CAG-C AG-3' (SEQ ID NO: 71) or5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 72).

[0034] In embodiment, the ASO comprises the sequence:5 '-C AG-CAG-C AG-3' (SEQ ID NO: 68) or5'-C AG-CAG-CAG-CAG-3' (SEQ ID NO: 69).

[0035] In embodiments the ASO comprises the sequence 5 '-C AG-CAG-C AG-3'.

[0036] In embodiments the ASO comprises the sequence 5'-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 68).

[0037] In embodiments the ASO comprises the sequence 5'-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 68).

[0038] In embodiments the ASO comprises the sequence 5'-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 69).

[0039] In embodiments the ASO comprises the sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 70).

[0040] In embodiments the ASO comprises the sequence 5 '-CAG-C AG-CAG-C AG-CAG-CAG-CAG-3' (SEQ ID NO: 71).

[0041] In embodiments the ASO comprises the sequence 5 '-CAG-CAG-C AG-CAG-C AG-CAG-CAG-CAG-3' (SEQ ID NO: 72).

[0042] In embodiments the ASO comprises the sequence 5 '-CAG-C AG-CAG-C AG-CAG-CAG-C AG-CAG-C AG-3' (SEQ ID NO: 73).

[0043] In embodiments the ASO comprises the sequence 5 '-CAG-C AG-CAG-C AG-C AG-CAG-C AG-CAG-CAG-CAG-3' (SEQ ID NO: 74).

[0044] In embodiments, an ASO that includes CAG repeats may include additional nucleotide sequences on the 5' end, 3' end, or both, of the CAG repeat. In embodiments, the additional nucleotide sequences may have 80% to 100% or 95% to 100% complementarity to portions of the target DMPK transcript to which they hybridize. The additional nucleotide sequences may be added to a CAG repeat nucleotide sequence to increase the selectivity of the ASO for hybridizing to target DMPK transcript.

[0045] The ASOs described herein may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, interms of absolute stereochemistry, as (R) or (S); α or β; or as (D) or (L). Included in the ASOs provided herein are all such possible isomers, as well as their racemic and optically pure forms.

[0046] The efficacy of an A SO or a compound that comprises an ASO may be assessed by evaluating the antisense activity effected by their administration. Antisense activity refers to any detectable and / or measurable activity attributable to the hybridization of an ASO to its target nucleotide sequence. Such detection and / or measuring may be direct or indirect. In embodiments, antisense activity is assessed by detecting and or measuring the amount of misspliced and / or correctly spliced transcripts of various genes known to be mis-spliced in the DM1 disease state. For example, in DM1, several downstream gene transcripts are mis-spliced, and the mis-spliced genes are associated with the disease phenotype. As such, the antisense activity of an ASO or a compound that comprises an ASO can be assessed by measuring the splicing correction of the mis-spliced transcripts associated with the disease state. The splicing correction can be assessed, for example, by measuring the amount of one or more mis-spliced gene transcripts, the amount of one or more correctly spliced gene transcripts, or both.

[0047] ASOs are nucleosides linked through internucleoside linkages. Nucleosides include a pentose sugar (e.g., ribose or deoxyribose) a sugar substitute, or a modified sugar and a nitrogenous base (nucleobase also called a base) covalently attached to sugar, sugar substitute, or modified sugar. The naturally occurring nucleobases found in DNA and / or RNA are adenine (A), guanine (G), thymine (T), cytosine (C), and uracil (U). The naturally occurring sugars found in DNA and / or RNA are deoxyribose (DNA) and ribose (RNA). The naturally occurring internucleoside linkage is a phosphodiester. In embodiments, the ASO may have all natural sugars, natural bases, and natural internucleoside linkages.

[0048] Chemically modified nucleosides and / or modified internucleoside linkages can be incorporated into ASOs. Such modifications can enhance one or more properties, such as nuclease resistance, pharmacokinetics, or affinity for a target gene or target transcript. Nonlimiting examples of modified nucleosides and modified internucleoside linkages are shown in FIG. 1 (“BASE”, “Bl”, and “B2” are nucleobases).

[0049] In general, a nucleobase is any group that contains one or more atoms or groups of atoms capable of hydrogen bonding to a base of another nucleic acid. In addition to natural nucleobases, many modified nucleobases or nucleobase mimetics known to those skilled in the art are amenable with the compounds described herein. The terms modified nucleobase andnucleobase mimetic can overlap but generally a modified nucleobase refers to a nucleobase that is fairly similar in structure to the parent nucleobase, whereas a nucleobase mimetic generally includes more complicated structures Examples of modified nucleobases include 2 -thiodeoxythymine (see structure 4 in FIG. 1) 7-deaza purine 5-mehtyl cytosine, G-clamp. An example of a nucleobase mimetic is tricyclic phenoxazine nucleobase mimetic. Methods for preparation of the above noted modified nucleobases are well known to those skilled in the art.

[0050] In embodiments, an ASO comprises one or more modified nucleosides having a modified sugar moiety. The furanosyl sugar ring of a natural nucleoside can be modified. A furanosyl sugar ring may be modified in any suitable manner, including, but not limited to, addition of a substituent group, bridging of two non-geminal ring atoms to form a bicyclic nucleic acid (BNA), and substitution of an atom or group such as -S-, -N(R)- or -C(R1)(R2) for the ring oxygen at the 4'-position. Modified sugar moieties are well known and can be used to alter, typically increase, the affinity of the ASO for its target and / or increase nuclease resistance. A representative list of modified sugars include but is not limited to non-bicyclic substituted sugars, especially non-bicyclic 2 '-substituted sugars having a 2'-F, 2'-OCH3 or a 2'-O(CH2)2-OCH3 substituent group (see structures 5 to 8 of FIG. 1 for examples), and 4'-thio modified sugars. The ring of a sugar can be opened, for example between the 2' and 3' position, to result in an unlocked nucleotide (see structure 14 of FIG. 1). Sugars can also be replaced with a sugar substitute (also a modified sugar), for example, a morpholino ring, or a methylenemorpholine (FIG. 2, structure 1) ring, among others.

[0051] In embodiments, an ASO may include one or more bicyclic modified sugars (BNA's), such as, for example, LNA (4'-(CH2)-O-2' bridge, see structure 9 of FIG. 1); 2'-thio-LNA (4'- (CH2)-S-2' bridge); tricyclo DNA (see structure 11 of FIG. 1) 2'-amino-LNA (4'-(CH2)-NR-2' bridge); ENA (4'-(CH2)2-O-2' bridge), 4'-(CH2)3-2' bridged BNA; 4'-(CH2CH(CH3))-2' bridged BNA; cEt (4'-(CH(CH3)-O-2' bridge, see structure 10 of FIG. 1); and cMOE BNAs (4'-(CH(CH2OCH3)-O-2' bridge).

[0052] In embodiments, an ASO may include one or more locked nucleic acids (LNAs) in which the 2'-hydroxyl group of the ribosyl sugar ring is linked to the 4' carbon atom of the sugar ring thereby forming a 2'-C,4'-C-oxymethylene linkage resulting in a bicyclic sugar moiety. The synthesis and preparation of the LNA monomers adenine, cytosine, guanine, 5-methyl-cytosine, thymine and uracil, along with their oligomerization, and nucleic acid recognition propertieshave been described (Koshkin et al., Tetrahedron, 1998, 54, 3607-3630). LNAs and preparation thereof are also described in WO 98 / 39352 and WO 99 / 14226.

[0053] In embodiments, an ASO has one or more modified internucleoside linkages.Internucleoside linking groups link the nucleosides (natural or modified) monomer units of an oligonucleotide together. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, vinyl phosphonates (see structure 15 of FIG. 1), alkylphosphonates (see structure 16 of FIG. 1), phosphoramidate, phosphorodiamidate (see structure 3 of FIG. 1), and phosphorothioates (see structures 1, 17, and 18 of FIG. 1). Representative non-phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (-CH2-N(CH3)-O-CH2-), thiodiester (-O-C(O)-S-), thionocarbamate (-O-C(O)(NH)-S-); siloxane (-O-Si(H)2-O-); and N,N'-dimethylhydrazine (-CH2-N(CH3)-N(CH3)-). ASOs having non-phosphorus internucleoside linking groups are referred to as oligonucleosides. Modified internucleoside linkages, compared to natural phosphodiester linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotides Intemucleoside linkages having a chiral atom can be prepared racemic, chiral, or as a mixture. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing linkages are well known to those skilled in the art.

[0054] In embodiments, a phosphate group can be linked to the 2', 3', or 5' (or 6', for a 6 membered ring, such as a methylenemorpholine ring) hydroxyl moiety of the sugar (or modified sugar). In forming oligonucleotides, the phosphate groups covalently links adjacent nucleosides to one another to form a linear polymeric compound. Within oligonucleotides, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The natural linkage of an RNA or DNA backbone is a 3' to 5' phosphodiester linkage. In this linkage, a 5' phosphate group of a nucleotide is linked to the 3' hydroxy of the adjacent 5' nucleotide in a phosphodiester bond.

[0055] In embodiments, the ASO is a phosphorodiamidate morpholino oligomer (PMO). A PMO has nucleosides that include a methylene morpholine ring conjugated to nucleobase (see structure 1 of FIG. 2). The PMO nucleoside monomers units are coupled through phosphorodiamidate intemucleoside linkages (see structure 2 of FIG. 2). The 6' terminal nucleotide (equivalent to the5' terminal end) of a PMO may lack a 5' phosphorus containing group. For example, the 6' terminal nucleotide of a PMO may have 6' hydroxyl group. FIG. 2, structure 2, shows a three nucleotide PMO. The 6' nucleotide has a terminal 6' hydroxyl group. The 3' nucleotide has 3' terminal NH group. The 3' terminal NH group can be used to conjugate a PMO to a delivery construct using, for example, amide chemistry. PMOs are uncharged nucleic acid analogs that bind to a target nucleic acid through base pairing. As uncharged, or net neutral charged, oligonucleotides, PMOs are particularly effective for intracellular delivery when conjugated to a delivery construct of the present disclosure.

[0056] In embodiments, the cargo is a PMO of the structurewhere X is an integer from 4 to 8 (SEQ ID NOS: 75, 76, 77, 78, and 79). In embodiments, X is an integer from 4 to 6 (SEQ ID NOS: 75, 76, and 77). In embodiments, X is 4 or 5 (SEQ ID NOS: 75 and 76). In embodiments, X is 5 or 6 (SEQ ID NOS: 76 and 77), In embodiments, X is 4 (SEQ ID NO: 75). In embodiments, X is 5 (SEQ ID NO: 76). In embodiments, X is 6 (SEQ ID NO: 77).

[0057] In embodiments, the cargo is a PMO. In one or more embodiments, the cargo is a PMO and comprises any ASO sequence disclosed herein. In embodiments, the cargo is a PMO such as any ASO sequence disclosed herein.

[0058] In embodiments, the ASO is a peptide nucleic acid (PNA). PNAs have a backbone of N-(2-aminoethyl) glycine monomers conjugated via amide bonds. Each N-(2-aminoethyl) glycine monomer includes a nucleobase attached via a methyl carbonyl linker. FIG. 3 shows a PNAstructure. The PNA includes an N-terminus and an N-terminal nucleobase (Bn). The N-terminus of a PNA can also be described as the 5' end of a PNA The PNA includes a C-terminus and a C-terminal nucleobase (Bc). The C-terminus of a PNA can also be described as the 3' end of a PNA. Between the N-terminus and the C-terminus, the PNA includes one or more nucleobases (Bn-Bc) each nucleobase attached to a N-(2-aminoethyl) glycine repeat monomer.

[0059] In one or more embodiments, the ASO is a PNA. In one or more embodiments, the ASO is a PNA and comprises any ASO sequence disclosed herein. In one or more embodiments, the ASO is a PNA such as any ASO sequence disclosed herein.

[0060] The compounds of the present disclosure include an ASO conjugated to a delivery construct. The delivery construct, also called an endosomal escape vehicle (EEV), is designed to facilitate cell penetration and / or endosomal escape. The delivery construct comprises a cyclic cell penetrating peptide (cCPP) and exocyclic amino acids and / or peptide components

[0061] An amino acid is a compound of theformula, or where q is 0 or 1 and R is a side chain that is H or an organic group that has a molecular weight of less than 300 g / mol. An organic group is any motif that comprises carbon and hydrogen atoms, and optionally, one or more nitrogen atoms, sulfur atoms, oxygen atoms, or any combination thereof. When q is 0, the amino acid is an alpha-amino acid since the amino group is attached to the alpha carbon of the carbonyl. When q is 1, the amino acid is a beta-amino acid since the amino group is attached to the beta carbon of the carbonyl. When q is 1, R can be coupled to the alpha carbon of the carbonyl (beta-2-amino acid) or the beta carbon of the carbonyl (beta-3-amino acid). If present, the stereocenter of the amino acid can be L or D. An amino acid may be a natural amino acid or an unnatural amino acid. The term natural amino acid refers to the L- and D-forms of the 20 proteogenic amino acids including arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, and tryptophan. The term unnatural amino acid refers to the L- and D-forms of amino acids that include a side chain that is different from the natural amino acids, a side chain that is attached to the amino group of the amino acid, an aminoacid having a methyl substituent attached to the alpha or beta carbon in addition to another side chain being attached to the alpha or beta carbon, or any combination thereof. Examples of unnatural amino acids include, but are not limited to, 6-N-methyllysine; 6-N,6-N-dimethyllysine; 6-N,6-N,6-N-trimethyllysine; citrulline; 3-(2-naphthyl)-alanine; 3-(l-naphthyl)-alanine; 3-(3- benzothienyl)-alanine; tetrahydro-isoquinoline-3-carboxylic acid (Tic); 2-furylalanine; 2-thienylalanine; biphenylalanine; homoarginine;fluorotryptophan (e.g., 5-fluorotryptophan); fluorotyrosine (3 -fluorotyrosine);N OH OHH2N H2Niodophenylalanine; O (2-pyridylal anine; 2-pyri di ne); O (3-CN,0H OHH2N H2Npyridylalanine; 3-Pyr); o (2-pyridylalanine; 4-Pyr); O (Tyr(Phe));.0... HN. „ NH, NHNHA. OH H2N' r r' o A OHN.¥ HN. ¥O(Tyr(Ph)); °H (N(Arg)); and ((N(Lys)).

[0062] The terms “amino acid side chain” or “side chain” refer to the characterizing R substituent bound to the alpha-carbon, beta-carbon, or the amino group of an amino acid.

[0063] An amino acid may be incorporated into a larger compound via one or two amide bonds. When covalently coupled to a larger compound by one or two amide bonds, the amino acid may be referred to as an amino acid residue or as an amino acid.

[0064] Amino acids and / or amino acid residues may be referred to using their full name, their conventional three letter abbreviation, or their conventional one letter abbreviation. When using the one letter abbreviation, capital letters indicate L-amino acids or residues, and lower-case letters indicate D-amino acids or residues. For example, arginine may be referred to as Arg, R, or r. Various amino acids and their abbreviations are listed in Table 1.Table 1.Amino Acid Abbreviations Abbreviations L-amino acid D-amino acid Alanine Ala (A) ala (a) Arginine Arg (R) arg (r ) Asparagine Asn (N) asn (n) Aspartic acid Asp (D) asp (d) Cysteine Cys (C) cys (c) Citrulline Cit cit Cyclohexylalanine Cha cha2,3-diaminopropionic acid Dap dap4-fluorophenylalanine 4F-Phe 4F-phe2-furyl alanine 2-FurA 2-fura Glutamic acid Glu (E) glu (e) Glutamine Gln (Q) gin (q) Glycine Gly (G)N-methylated glycine Gly(N-me) (G(N-me)) - Histidine His (H) his (h) Homoarginine HoArg Hoarg Isoleucine Ile (I) ile (i) Leucine Leu (L) leu (l)Lysine Lys (K) lys (k)Methi onine Met (M) met (m)3-(2-naphthyl)-alanine Nal, 2-Nal nal, 2-nal, or d2-nal3 -( 1 -naphthyl)-al anine 1-Nal 1-nal Norleucine Nle nle Phenylalanine Phe (F) phe (f)N-methylated phenylalanine Phe(N-me); (F(N-me) phe(N-me); (f(N- me) Phenylglycine Phg phgProline Pro (P) pro (p) Sarcosine Sar sarSerine Ser (S) ser (s) Threonine Thr (T) thr (y) Tyrosine Tyr (Y) tyr (y)Try pt ophan Trp (W) trp (w)Amino Acid Abbreviations Abbreviations L-amino acid D-amino acid Tetrahydro-isoquinoline-3-carboxylic acid Tic tic Thienylalanine ThienA thiena Valine Vai (V) val (v) Tert-butyl-alanine Tie tie Penicillamine Pen Pen Homoarginine Homo Arg homoarg Methyl-leucine MeLeu meLeu3-(3-benzothienyl)-alanine Bta bta4,4'-Biphenylalanine (biphenylalanine) Bip bip6-N -M ethyl 1 y si n e K(me) k(me)6-N,6-N-Dimethyllysine K(me)2 k(me)26-N, 6-N, 6-N-Dimethylly sine K(me)3 k(me)2N-methyl arginine R(rae) r(me) Ornithine Oro oro2-pyridylalanine 2-Pyr 2-pyr3-pyridylalanine 3-Pyr 3-pyr4-pyridylalanine 4-Pyr 4-pyr Tyr(Ph); Y(Ph) tyr(Ph); y(Ph)X.. OH0Phe(3-CN); F(3-CN) phe(3-CN); f-(3- CN)A „OHH2N Y0CN Phe(4-CN), F(3-CN) phe(4-CN); f-(4- CN) XX03-cy anophenylalanine5 -Fluorotyrpt ophan Trp(5-F); W(5F) trp(5-F); w(5F)lodophenylalainine Phe(I), F(I) Phe(I), f(I)Amino Acid Abbreviations Abbreviations L-amino acid D-amino acid Agp agpTa2-amino-3-guanidinopropionic acidPara-chlorophenylalanine, 4-chloro- Pepa pepa or dPcpa phenylal anine (F encl onine)O" OH, A 'J HH,cr2Homophenylalanine Hph hph or dHph Y A 0k<>x1 ' JIy OHNH2Phenylglycine Ph 0g phg or dPhg Y A 0Y k A.YOHHfc h „ ^H2O HN. A OHN-(3 -guani di noprc >pyl)glycine, N(Arg),NIB A N(r)NH2JY 0HN Ji'OHN-(4-aminobutyl)glycine, N(Lys), N(K),N(k)

[0065] In embodiments, the amide nitrogen of an amino acid residue in a compound of the present disclosure can be methylated (-CH3). Such amino acid residues can be described as theN-methylated amino acid name or the amino acid shorthand followed by (N-me), me, or (me). For example, a compound of the present disclosure can include N-methylated phenylalanine (F(N-me), f(N-me)), or N-methylated glycine (G(N-me) N-methylated arginine (R(N-me), r(N-me)).

[0066] The cCPP and / or the exocyclic amino acids or exocyclic peptides can include one or more hydrophilic amino acids, one or more hydrophobic amino acids, or both. Amino acids can be grouped as hydrophobic or hydrophilic based on the chemical composition of their side chain.

[0067] Amino acids having a side chain that is charged in an aqueous solution at pH 7.4 are hydrophilic. Such amino acids can be referred to as charged amino acids or charged amino acid residues. Examples of charged amino acids include, but are not limited to, the alpha or betai, N HIt.. OH A ob, A_amino acids of histidine; arginine; homoarginine;&; OH;H2W HHM A, OHO; ornithine; 6-N-methy lysine; 6-N,6-N-dimethyllysine; 6-N,6-N,6-N-K"' 9dimethyllysine; lysine;' '; aspartic acid; citrulline; ornithine; and glutamic acid

[0068] Amino acids having an uncharged side chain that comprises an aromatic group are hydrophobic. In some embodiments they are an alpha or beta amino acid. Such amino acids can be referred to as aromatic amino acids or aromatic amino acid residues Examples of aromatic amino acid include, but are not limited to, the alpha or beta amino acids of phenylalanine, tryptophan; tyrosine; phenylalanine; 3-(2-naphthyl)-alanine; 3-(l-naphthyl)-alanine; 3-(3-benzothienyl)-alanine; tetrahydro-isoquinoline-3-carboxylic acid; 2-furyl lanine; 2 -thienylal; biphenylalanine; iodophenylalanine, fluorotryptophan (e.g., 5 -fluorotryptophan); fluorotyrosine.1, OHy(3 -fluorotyrosine);® (2-pyridylalanine; 2-pyridine);(3-pyridylalanine; 3-Pyr); (2-pyridylalanine; 4-Pyr);para-chlorophenylalanine; homophenylalanine; and phenylglycine.

[0069] Amino acids having a hydrocarbon side chain that is not charged and does not include an aromatic group are hydrophobic. Such amino acids can be referred to as uncharged, not aromatic, hydrocarbon amino acids or residues. Examples of uncharged, not aromatic, hydrocarbon amino acids include, but are not limited to, glycine, proline, and the alpha or beta amino acids of alanine, valine, leucine, and isoleucine.

[0070] Amino acids that have an uncharged side chain that does not include an aromatic group and has a ratio of carbon atoms to heteroatoms of 1.5:1 or less are hydrophilic. Examples of such amino acids include, but are not limited to, the alpha or beta amino acids of serine, threonine, asparagine, and glutamine.

[0071] Amino acids that have an uncharged side chain that does not include an aromatic group and has a ratio of carbon atoms to heteroatoms of greater than 1.5:1 are hydrophilic.

[0072] The compounds of the present disclosure can be of Formula I:Formula I:R20“(AA1)J?(L1)^NY ^(AA2>5(L2)s(AA3),r(L3)s(AA4ti-(M^jcar0o Pk '< V NHor a pharmaceutically acceptable salt thereof,where:ORd0is H or ’al, a2, a3, and a4 are each independently 0 or 1 and at least 1 of a2, a3, and a4 is 1;bl, b2, and b3 are each independently 0 or I and at least one of bl, b2, and b3 is 1;LI, L2, and L3 are each independently a linker covalently coupling two adjacent motifs, AA1 is an amino acid residue or a peptide that comprises 2 to 10 amino acid residues;AAA2, AA3, and AA4 are each independently an amino acid residue or a peptide that comprises 2 to 6 amino acid residues, where at least one of AA2, A A3, and A4 present in the compound comprises a hydrophobic or a hydrophilic amino acid;n is an integer from 1 to 3;y is an integer from 1 to 5;ml is 0 or 1;o6 JUM' comprises‘, or a heteroaryl where t is an integer from 0 to 10;R1, R2, R3, R4, R5, R6, and R7are each independently an amino acid side chain;cargo comprises an A SO having a sequence that comprises at least one CAG repeat.

[0073] Formula I comprises a cyclic cell penetrating peptide (cCPP). In Formula I the cCPP comprises the amino acid residues characterized by R1, R2, R3, R4, R5, R6, and R7. In Formula I, the amino acid residues or peptides of AA1, AA2, AA3, and AA4 are exocyclic amino acid residues or peptides.O

[0074] In embodiment R20isU. For example, in embodiments when al is 1, the amino group of the N-terminal amino acid residue of AA1 can be acetylated (-C(O)-CH3). In other embodiments when al is 1, the amino group of the N-terminal amino acid of AA1 is not acetylated.

[0075] al, a2, a3, and a4 are each independently 0 or 1 where at least one of a2, a3, and a4 is 1. In embodiments, at least one of a2 and a3 is 1. a l can be 1. al can be 0. a2 can be 1. a2 can be 0. a3 can be 1. a3 can be 0.

[0076] In embodiments, al is 1, and only one of a2, a3, and a4 is 1. In embodiments, al is 0, a2 is 0, a3 is 1, and a4 is 0. In embodiments, al is 1, a2 is 0, a3 is 1, and a4 is 0 In embodiments, al is 1, a2 is 0, a3 is 1, and a4 is 1. In embodiments, al is 0, a2 is 0, a3 is 1, and a4 is 1.

[0077] In embodiments, al is 1, a2 is 1, a3 is 1, and a4 is 0. In embodiments, al is 0, a2 is 1, a3 is 1, and a4 is 0. In embodiments, al is 1, a2 is 1, a3 is 0, and a4 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, and a4 is 0.

[0078] bl, b2, b3, and b4 are each independently 0 or 1 where at least one of bl, b2, and b3 is 1. In embodiments, at least one of bl and b2 is 1. bl can be 1. bl can be 0. b2 can be 1. b2 can be 0. b3 can be 1. b3 can be 1 In embodiments, bl is 1, b2 is 1, and b3 is 0. In embodiments, bl is 0, b2 is 1, and b3 is 0. In embodiments, bl is 1, b2 is 1, and b3 is 1. In embodiments, bl is 0, b2 is 1, and b3 is 1.

[0079] In embodiments, al is 1, a2 is 1, a3 is 0, a4 is 0, bl is 1, b2 is 1, and b3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, bl is 1, b2 is 1, and b3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, bl is 0, b2 is 1, and b3 is 0.

[0080] In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 0, bl is 1, b2 is 1, and b3 is 1. In embodiments, al is 0, a2 is 0, bl is 1, b2 is 1, and b3 is 1, In embodiments, al is 0, a2 is 0, bl is 0, b2 is 1, and b3 is 1.

[0081] In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 1, bl is 1, b2 is 1, and b3 is 1. In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 1, bl is 1, b2 is 1, and b3 is 1. In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 1, b l is 0, b2 is 1, and b3 is 1

[0082] In embodiments, al is 1, a2 is 1, a3 is 1, a4 is 0, bl is 1, b2 is 1, and b3 is 0, In embodiments, al is 1, a2 is 1, a3 is 1, a4 is 0, bl is 1, b2 is 1, and b3 is 0. In embodiments, al is 1, a2 is 1, a3 is 1, a4 is 0, bl is 0, b2 is 1, and b3 is 0.In embodiments, al is 1, a2 is 1, a3 is 0, a4 is 0, bl is 1, b2 is 1, and b3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, a4 is 0, bl is 1, b2 is 1, and b3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, a4 is 0, bl is 0, b2 is 1, and b3 is 0.

[0083] The compounds of the present disclosure can be of Formula II:Formula II:H o Y R20™(AA1)^-(L1)^ 'Y' ^(L2)™(AA3)~~(L3)~~(AA4J~~(L4) — (W)~- cargo ' 4 NH cwor a pharmaceutically acceptable salt thereof,where:R20i s H oral is 0 or 1;b l is 0 or 1;LI, L2, L3, and L4 are each independently a linker covalently coupling two adjacent motifs; AAl is an amino acid residue or a peptide comprising 2 to 10 amino acid residues;AA3 and AA4 are each independently an amino acid residue or a peptide that comprises 2 to 6 amino acid residues, where at least one of AA3 and AA4 present in the compound comprises a hydrophobic or a hydrophilic amino acid;n is an integer from 1 to 3;y is an integer from 1 to 5;ml is 0 or 1;o< isM' comprises' 't '. or a heteroaryl where t is an integer from 0 to 10;R1, R2, R3, R4, R’, R°, and R7are each independently an amino acid side chain; andcargo comprises an ASO having a sequence that comprises at least one CAG repeat.

[0084] Formula II comprises a cyclic cell penetrating peptide (cCPP). In Formula II, the cCPP comprises the amino acid residues characterized by R1, R, R3, R4, R5, R6, and R7. In Formula II, the amino acid residues or peptides of AA1, AA2, AA3, and AA4 are exocyclic amino acid residues or peptides.

[0085] In embodiment R20isxS'. For example, in embodiments when al is 1, the amino group of the N-terminal amino acid residue of AA1 can be acetylated (-C(O)-CH3). In other embodiments when al is 1, the amino group of the N-terminal amino acid of AA1 is not acetylated.

[0086] al is 0 or 1. al can be 1 al can be 0.

[0087] bl is 0 or 1. bl can be 1. bl can be 0.

[0088] In embodiments al is 0 and bl is 0. In embodiments al is 0 and bl is 1. In embodiments al is 1 and bl is 0. In embodiment, al is 1 and bl is 1.Linker: LI, L2, L3, L4 and combinations thereof

[0089] LI, L2, L3, and L4 are each independently a linker covalently coupling two adjacent motifs.

[0090] LI, L2, L3, and L4 (if present) can each independently comprise, for example, one or more ethers, one or more esters, one or more ketones, one or more amides, one or more alkylenes, or any combination thereof. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more amides. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more ethers. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length Cl to C5. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length Cl, C2, C3, C4, or C5. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length Cl. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length C2. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length C3, In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length C4. In embodiments, LI, L2, L3, and L4 (if present) can each independently comprise one or more alkylenes of length C5

[0091] In embodiments, LI, L2, L3, and L4 (if present), can each independently comprise one or more poly(ethylene glycol) (PEG) units (-CH2-CH2-O-). In embodiments, one or more of LI, L2, L3, and L4 present in the compound can each independently comprise 1 to 14 PEG units. In embodiments where any of LI, L2, L3, and L4 comprise more than one PEG unit, the PEG units can be continuous or discontinuous. For example, in embodiments where any of LI, L2, L3, and L4 comprise more than one PEG unit, the PEG units or groups of PEG units may be separated with a dialkyl, an amide, an ester, or a combination of a dialkyl and amide or a dialkyl and an ester.

[0092] In embodiments, one or more of LI, L2, L3, and L4 present in the compound compriseswwhere p is an integer from 1 to 14 and s is and integer from 1 to 4. s can be 1. s can be 2. s can be 3. s can be 4. In embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,or 14 and s can be 1, 2, 3, or 4. In embodiments, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 and s can be 1 or 2, In embodiments, p is 2, 4, 6, 8, 10, 12, or 14 and s is I. In embodiments, p is 2, 4, 6, 8, 10, 12, or 14 and s is 2. In embodiments, p is 2, 4, 8, or 12 and s is 1. In embodiments, p is 2, 4, 8, or 12 and s is 2. In embodiments, p is 2 and s is 1. In embodiments, p is 2 and s is 2. In embodiments, p is 4 and s is 1, In embodiments, p is 4 and s is 2. In embodiments, p is 8 and s is 1. In embodiments, p is 8 and s is 2. In embodiments, p is 8 and s is 2. In embodiments, p is 12 and s is 1. In embodiments, p is 12 and s is 2.

[0093] In embodiments,, L I compriseswwhere p and s are defined herein.\ A,In embodiments, b2 is 1 and L2 compriseswhere p and s are definedherein. In embodiments, L2 compriseswhere p and s are defined herein.op |Zp >4In embodiments, b3 is 1 and L3 compriseuwhere p and s are defined herein. In embodiments, bl is 1, b2 is 1, b3 is 0, and LI and L2 both includewhere p and s are defined herein and can be the same or different for LIand L2. In embodiments, bl is 0, b2 is 1, b3 is 0, and LI compriseswhere p and s are defined herein.

[0094] In embodiments, b l is 1, b2 is 1, b3 is 1, and LI, L2, and L3 all compriseOL '''s'lp ''*> 0 where p and s are defined herein and can be the same or different for LI, L2, and L3. In embodiments, bl is 0, b2 is 1, b3 is 1, and L2 and L3 both comprisewhere p and s are defined herein and can be the same or different for LI, and L2.

[0095] In embodiments, bl is 1 and LI, L2, L3, and L4 all comprisewhere p and s are defined herein and can be the same or different for LI, L2, L3, and L4. In H / ■: -N I wembodiments, bl is 0 and L2, L3, and L4 all comprisevwhere p and s are defined herein and can be the same or different for L2, L3, and L4.Amino Acid(s): AA1

[0096] AA1, when present (al is 1), is a single amino acid residue or a peptide of 2 to 10 amino acid residues.

[0097] AA1 comprises 1 to 10 amino acid residues e.g,, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In embodiment, AA1 comprises 2 to 8 amino acid residues or 2 to 6 amino acid residues. In embodiments, AA1 is a single amino acid residue. In embodiments, AA1 is a 2 -residue peptide. In embodiments, AA1 is a 3-residue peptide. In embodiments, AA1 is a 4-residue peptide. In embodiments, AA1 is a 5-residue peptide. In embodiments, AA1 is a 6-residue peptide. In embodiments, AA1 is a 7-residue peptide. In embodiments, AA1 is an 8-residue peptide. In embodiments, AA1 is a 9-residue peptide. In embodiments, AA1 is a 10-residue peptide.

[0098] The amino acid residues in AA1 can have D- or L-stereochemistry. The amino acid residues of AA1 may all be D-amino acids. The amino acid residues of AA1 may all be L-amino acids. The amino acid residues of AA1 may be a combination of D-amino acids and L-amino acids.

[0099] In embodiments, AAI comprises one of the following sequences: K, KK, RK, KFK, KRK, KKK, KKRK (SEQ ID NO. I), KKFRK (SEQ ID NO: 2), KGKRK (SEQ ID NO: 3), KKGRK (SEQ ID NO: 4), KKKGK (SEQ ID NO: 5), KKRKG (SEQ ID NO: 6), KKRKK (SEQ ID NO: 7), KKTRK (SEQ ID NO: 8), TKKRK (SEQ ID NO: 9), pkkkrkv (SEQ ID NO: 10), kkkRK (SEQ ID NO: 11), kkkrk (SEQ ID NO: 12), KKKRK (SEQ ID NO: 13), K(me)-K(me)- K(me)-R(me)-K(me) (SEQ ID NO: 14), TKKRK (SEQ ID NO: 15), KKKRKF (SEQ ID NO: 16), KKKRKR (SEQ ID NO: 17), PKKKRKV (SEQ ID NO: 18), RBKKRB (SEQ ID NO: 19), RBRRBR (SEQ ID NO: 20), YArVRRrGPR (SEQ ID NO: 21), RFGRK (SEQ ID NO: 22), KKKHH (SEQ ID NO: 15), KBKBKBRBK (SEQ ID NO: 23), RFKKRFK (SEQ ID NO: 24), RBKKBR (SEQ ID NO: 80), N(Lys)-N(Lys)-N(Lys)-N(Arg)-N(Lys) (SEQ ID NO: 25), N(Arg)-B-N(Arg)-N(Arg)-B-N(Arg) (SEQ ID NO: 26), or N(Lys)-N(Lys)-N(Lys)-N(Arg)-N(Lys) (SEQ ID NO: 27).

[0100] In embodiments, AAI comprises is K. In embodiment, AA1 includes comprises KK. In embodiments,. A Al includes comprises RK. In embodiments, A l comprises RFK. In embodiments, AA1 comprises KRK. In embodiments, AA1 comprises KKK. In embodiments, AAI comprises KKRK (SEQ ID NO: 1). In embodiments, AA1 comprises KKFRK (SEQ ID NO: 2). In embodiments, AAI comprises KGKRK (SEQ ID NO: 3). In embodiments, AA1 comprises KKGRK (SEQ ID NO: 4). In embodiments, AAI comprises KKKGK (SEQ ID NO: 5). In embodiments, AAI comprises KKRKK (SEQ ID NO: 7). In embodiments, AAI comprises KKRKG (SEQ ID NO: 6). In embodiments, AAI comprises KKTRK (SEQ ID NO: 8). In embodiments, AAI comprises TKKRK (SEQ ID NO: 9). In embodiments,? XA1 comprises pkkkrkv (SEQ ID NO: 10)In embodiments, AAI comprises kkkRK (SEQ ID NO: 11). In embodiments, AAI comprises kkkrk (SEQ ID NO: 12). In embodiments, AAI comprises kkkRK (SEQ ID NO: 11). In embodiments, AAI comprises KKKRK (SEQ ID NO: 10). In embodiments, AAI comprises KKKRK (SEQ ID NO: 13). In embodiments, AAI comprises KKRK (SEQ ID NO: 1). In embodiments, AAI comprises K(me)-K(me)-K(me)-R(me)-K(me) (SEQ ID NO: 14). In embodiments, AAI comprises TKKRK (SEQ ID NO. 15). In embodiments, AAI comprises KKKRKF (SEQ ID NO: 16). In embodiments, AAI comprises KKKRKR (SEQ ID NO: 17). In embodiments, AAI comprises PKKKRKV (SEQ ID NO: 18). In embodiments, AAI comprises RBKKRB (SEQ ID NO: 19). In embodiments, AAI comprises RBRRBR (SEQ ID NO: 20). In embodiments, AAI comprises YArVRRrGPR (SEQ ID NO: 21)In embodiments, AA1 comprises RFGRK (SEQ ID NO: 22). In embodiments, AA1 comprises KK. KHH (SEQ ID NO: 15) In embodiments, AA1 comprises KBKBKBRBK (SEQ ID NO: 23). In embodiments, AA1 comprises RFKKRFK (SEQ ID NO: 24). In embodiments, AA1 comprises RBKKBR (SEQ ID NO: 80). In embodiments, AA1 comprises N(Lys)-N(Lys)- N(Lys)-N(Arg)-N(Lys) (SEQ ID NO: 25). In embodiments, AA1 comprises N(Arg)-B-N(Arg)- N(Arg)-B-NfArg) (SEQ ID NO: 26).Amino Acid(s): AA2, AA3, AA4, and combinations thereof

[0101] AAA2, AA3, and AA4 are each independently an amino acid residue or a peptide that comprises 2 to 6 amino acid residues. The total number of amino acids in each of AA2, AA3, and AA4 can vary.

[0102] AA2 can include 1 to 6 amino acid residues. AA2 can include 1 amino acid residue. AA2 can include 2 amino acid residues. AA2 can include 3 amino acid residues. AA2 can include 4 amino acid residues. AA2 can include 5 amino acid residues. AA2 can include 6 amino acid residues.

[0103] AA3 can include 1 to 6 amino acid residues. AA3 can include 1 amino acid residue. AA3 can include 2 amino acid residues. AA3 can include 3 amino acid residues. AA3 can include 4 amino acid residues. AA3 can include 5 amino acid residues. AA3 can include 6 amino acid residues.

[0104] AA4 can include 1 to 6 amino acid residues. AA4 can include 1 amino acid residue. AA4 can include 2 amino acid residues. AA4 can include 3 amino acid residues. AA4 can include 4 amino acid residues. AA4 can include 5 amino acid residues AA4can include 6 amino acid residues.

[0105] The sum of amino acid residues in the combination of A2, A A3, and AA4 present in the compound can vary, for example, from 1 to 18. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 1 to 16. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 1 to 14. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 1 to 12. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 1 to 10. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 1 to 8. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 2 to 8. The sum ofamino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 2 to 6. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 2 to 4. The sum of amino acid residues in the combination of AA2, AA3, and AA4 present in the compound can be 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0106] In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 can comprise 1 to 6 amino acid residues. In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 comprises 1 amino acid residue. In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 comprises 2 amino acid residues. In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 comprises 3 amino acid residues. In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 comprises 4 amino acid residues. In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 comprises 5 amino acid residues. In embodiments when a2 is 0, a3 is 1, and a4 is 0, AA3 comprises 6 amino acid residues.

[0107] In embodiments when a2 is 0, a3 is 1, and a4 is 1, the sum of amino acid residues in AA3 and AA4 is 2 or 3. In embodiments when a2 is 0, a3 is 1, and a4 is 1, the sum of amino acid residues in AA3 and AA4 is 2. In embodiments when a2 is 0, a3 is 1, and a4 is I, the sum of amino acid residues in AA3 and AA4 is 3.

[0108] In embodiments of when a2 is 1, a3 is 1, and a4 is 0, the sum of amino acid residues in AA3 and AA4 is 2 to 6. In embodiments when a2 is 1, a3 is 1, and a4 is 0, the sum of amino acid residues in AA3 and AA4 is 3, In embodiments when a2 is 1, a3 is 1, and a4 is 0, the sum of amino acid residues in AA3 and AA4 is 4. In embodiments when a2 is 1, a3 is 1, and a4 is 0, the sum of amino acid residues in AA3 and AA4 is 5. In embodiments when a? is 1, a3 is 1, and a4 is 0, the sum of amino acid residues in AA3 and AA4 is 6.

[0109] In embodiments, the sum of amino acid residues in AA3 and AA4 is 2 to 6. In embodiments, the sum of amino acid residues in AA3 and AA4 is 3. In embodiments, the sum of amino acid residues in AA3 and AA4 is 4. In embodiments, the sum of amino acid residues in AA3 and AA4 is 5 In embodiments, the sum of amino acid residues in AA3 and AA4 is 6.

[0110] In embodiments when a2 is 1, a3 is 0, and a4 is 0, AA2 comprises 1 amino acid residue.

[0111] At least one of A A2, AA3, and AA4 present in the compound comprises at least one hydrophobic or hydrophilic amino acid residue. In embodiments, at least one of AA2, AA3, and AA4 present in the compound comprises at least one hydrophobic amino acid residue. In embodiments, at least one of AA2, A A3, and AA4 present in the compound comprises at least one hydrophilic amino acid residue.

[0112] In embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises two or more hydrophilic amino acid residues. In embodiments, the two or more hydrophilic amino acid residues may be a part of a single peptide in AA2, AA3, or AA4. For example, in embodiments where a2 is 1, a3 is 1, or a4 is 1, one or more of AA2, AA3, and AA4 can include a peptide having two or more hydrophilic amino acid residues. In embodiments one or both of AA3, and AA4 can include a peptide having two or more hydrophilic amino acid residues. Within a single AA2, AA3, or AA4 group present in a compound, the two or more hydrophilic amino acids may be contiguous or separated by one or more additional amino acid residues, such as one or more hydrophobic amino acid residues. In embodiments, the two or more hydrophilic amino acid residues may independently be present between AA2, AA3, and AA4 present in the compound. For example, in embodiments where a3 and a4 are 1, each of AA3 and AA4 can independently have one or more hydrophilic amino acid residues.Additionally, in embodiments where a2 and a3 are 1, each of AA2 and AA3 can independently have one or more hydrophilic amino acid residues. In embodiments, each of AA3 and AA4 can independently have one or more hydrophilic amino acid residues. In embodiments, each of AA2 and A A3 can independently have one or more hydrophilic amino acid residues.

[0113] In embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises at least one hydrophobic amino acid residue. In embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises two or more hydrophobic amino acid residues. In embodiments, the two or more hydrophobic amino acid residues may be a part of a single peptide in AA2, AA3, or AA4. For example, in embodiments where a2 is 1, a3 is 1, or a4 is 1, one or more of AA2, AA3, and AA4 can include a peptide having two or more hydrophobic amino acid residues. For example, in embodiments, AA3, AA4, or both can include a peptide having two or more hydrophobic amino acid residues. Within a single AA2, AA3, or AA4 group present in a compound, the two or more hydrophobic amino acids may be contiguous or separated by one or more additional amino acid residues, such as one or more hydrophilic amino acid residues. In embodiments, the two or more hydrophobic amino acid residues may independently be present in the combination of AA2, AA3, and AA4. For example, in embodiments where a3 and a4 are 1, each of AA3 and AA4 can independently have one or more hydrophobic amino acid residues Additionally, in embodiments where a2 and a3 are 1, each of AA2 and AA3 can independently have one or more hydrophobic amino acid residues. Inembodiments, AA3 and AA4 can each independently have one or more hydrophobic amino acid residues. In embodiments, AA3 and AA4 can each independently have one or more hydrophobic amino acid residues.

[0114] In embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises at least one hydrophilic amino acid residue and at least one hydrophobic amino acid residue.

[0115] The at least one hydrophilic amino acid residue and the at least one hydrophobic amino acid residue may be present in a single peptide in AA2, AA3, or AA4 present in the compound. For example, in embodiments where a2 is 1, AA2 can include at least one hydrophilic amino acid residue and at least one hydrophobic amino acid residue. In embodiments where a3 is 1, AA3 can include at least one hydrophilic amino acid residue and at least one hydrophobic amino acid residue. In embodiments where a4 is 1, AA4 can include at least one hydrophilic amino acid residue and at least one hydrophobic amino acid residue. In embodiments, AA3 can include at least one hydrophilic amino acid residue and at least one hydrophobic amino acid residue. In embodiments, AA4 can include at least one hydrophilic amino acid residue and at least one hydrophobic amino acid residue.

[0116] The at least one hydrophilic amino acid residue and the at least one hydrophobic amino acid residue may independently be present in at least two of AA2, AA3, and AA4 present in the compound. For example, in embodiments when at least two of a2, a3 and a4 are 1, the at least one hydrophobic amino acid residue and the at least one hydrophilic amino acid residue may independently be present between at least two of AA2, AA3, and AA4. In embodiments, the at the at least one hydrophobic amino acid residue and the at least one hydrophilic amino acid residue may independently be present between AA3 and AA4.

[0117] The combination of AA2, AA3, and AA4 present in a compound can have one or more hydrophilic amino acid residues and one or more hydrophilic amino acid residues. In some embodiments, the ratio of hydrophilic amino acid residues to hydrophobic amino acid residues in the combination of AA2, A A3, and AA4 present in the compound is 1 to I. For example, in embodiments, the combination of AA2, AA3, and AA4 present in the compound has the same number of hydrophobic amino acids and hydrophilic amino acids. In other embodiments, the ratio of hydrophilic amino acid residues to hydrophobic amino acid residues in the combination of AA2, AA3, and AA4 present in the compound is not 1 to 1 For example, in embodiments, inembodiments, the combination of AA2, AA3, and AA4 present in the compound has a different number of hydrophobic amino acids and hydrophilic amino acids.

[0118] In embodiments, the combination of AA2, AA3, and AA4 present in a compound has a greater number of hydrophilic amino acid residues than hydrophobic amino acid residues. As such, in embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises 1.1 to 5 hydrophilic amino acid residues or more for every 1 hydrophobic amino acid. For example, in embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises 2 hydrophilic amino acid residues and 1 hydrophobic amino acid residue; 3 hydrophilic amino acid residues and 1 or 2 hydrophobic amino acid residues; 4 hydrophilic amino acid residues,!, 2, or 3 hydrophobic amino acid residues; or 5 hydrophilic amino acid residues,!, 2, 3, or 4 hydrophobic amino acid residues

[0119] In some embodiments, the combination of AA2, AA3, and AA4 present in a has a greater number of hydrophobic amino acid residues than hydrophilic amino acid residues. As such, in embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises 1.1 to 3 hydrophobic amino acid residues for every 1 hydrophilic amino acid. For example, in embodiments, the combination of AA2, AA3, and AA4 present in the compound comprises 2 hydrophobic amino acid residues and 1 hydrophilic amino acid residue; 3 hydrophobic amino acid residues and 1 or 2 hydrophilic amino acid residues; or 4 hydrophobic amino acid residues and 2 or 3 hydrophilic amino acid residues.

[0120] One of more of AA2, AA3, and AA4 present in a compound can individually have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues of 1 to 1. For example, in embodiments when a2 is 1, AA2 can be a peptide having the same number of hydrophilic amino acid residues as hydrophobic amino acid residues. In embodiments, when a3 is 1, AA3 can be a peptide having the same number of hydrophilic amino acid residues as hydrophobic amino acid residues. In embodiments, when a4 is 1, AA4 can be a peptide having the same number of hydrophilic amino acid residues as hydrophobic amino acid residues. In embodiments, AA3 can be a peptide having the same number of hydrophilic amino acid residues as hydrophobic amino acid residues. In embodiments, AA4 can be a peptide having the same number of hydrophilic amino acid residues as hydrophobic amino acid residues.

[0121] One of more of AA2, AA3, and AA4 present in a compound of can individually have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is not 1 to 1.For example, in embodiments when a2 is 1, AA2 can be a peptide having a different number of hydrophilic amino acid residues and hydrophobic amino acid residues. In embodiments when a3 is 1, AA3 can be a peptide having a different number of hydrophilic amino acid residues and hydrophobic amino acid residues. In embodiments when a4 is 1, AA4 can be a peptide having a different number of hydrophilic amino acid residues and hydrophobic amino acid residues. In embodiments, AA3 can be a peptide having a different number of hydrophilic amino acid residues and hydrophobic amino acid residues. In embodiments, AA4 can be a peptide having a different number of hydrophilic amino acid residues and hydrophobic amino acid residues.

[0122] One of more of AA2, A A3, and AA4 present in a compound can individually have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is 1 to 1 and one or more of AA2, AA3, and AA4 present in the compound can individually have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is not 1 to I. For example, in embodiments where a2 is 1 or 0, a3 is 1, and a4 is 1, either AA2 or AA4 can have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is 1 to I and the AA2 or AA4 can have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is not I to 1. In embodiments where a2 is 1, a3 is 1, and a4 is 1 or 1, either AA2 or AA3 can have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is I to 1 and the AA2 or AA3 can have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is not 1 to 1. In embodiments, either AA3 or AA4 can have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is 1 to 1 and the AA3 or AA4 can have a ratio of hydrophilic amino acid residues to hydrophobic amino acid residues that is not I to 1.

[0123] In embodiments, each hydrophobic amino acid residue of each of AA2, AA3, and AA4 present in a compound is independently an aromatic amino acid residue; an uncharged, not aromatic, hydrocarbon amino acid residues; an amino acid residue that does not have a side chain, or any combination thereof. In embodiments, each hydrophobic amino acid residue of each of AA2, AA3, and A A4 present in the compound is independently an aromatic amino acid residue. In embodiments, each hydrophobic amino acid residue of each of AA2, AA3, and AA4 present in the compound is independently an uncharged, not aromatic, hydrocarbon amino acid residue or an amino acid residue that does not have a side chain. In embodiments, the combination of hydrophobic amino acid residues in the combination of each of AA2, AA3, andAA4 present in the compound is includes at least one aromatic amino acid residue and at least one amino acid residue having no side chain,[01241 In embodiments, each aromatic amino acid residue of each of AA2, AA3, and AA4 present in a compound is selected from L- or D-phenylalanine, L- or D-naphthylalanine, L- or D-3-benzotheinyl alanine, L- or D-biphenylalanine, L- or D-tyrosine, L-or D-2-pyridylalanine, L-or -D-3-pyridylalanine, L- or D-4-pyridylalanine, L- or D- $, L-or D-$, iodophenylalanine, L- or D- 5-fluorotyrptophan, L- or D-tyrosine, L- or D-tyrptophan, L- or D-parachlorophenylalanine, L- or D-homophenylalnine, or L- or D-phenylglyine. In embodiments, each an uncharged, not aromatic, hydrocarbon amino acid residue in each of AA2, AA3, and AA4 in the compound is L- or D-valine or L- or D-proline. In embodiments, each amino acid residue having a no side chain is selected from glycine and betaalanine.In embodiments, each hydrophobic amino acid residue of each of AA2, AA3, and AA4 present in a compound of is independently a charged amino acid. In embodiments, each charged amino acid residue hydrophobic in each of AA2, AA3, and AA4 in the compound is selected from L- or D- NH2HHA OHH2No Y arginine, L- or D-homoarginine, L- or D-w, L- or D- O, L- or D-lysine, L- or D-serine, L- of D-citrulline, or L- or D-glutamic acid.

[0125] In embodiments, the combination of AA2, AA3, and AA4 present in a compound comprises one or more hydrophilic amino acids independently selected from L- or D-arginine, L-NH2JrA OHH2Nor D-homo-arginine, L- or D- 0, L- or D, L- or D-citrulline, L-or D-lysine, L- or D-serine, L- or D-histidine, or L- or D-glutamic acid; and one or more hydrophobic amino acids independently selected from L-or D-phenyl alanine, L- or D-naphthylalanine, L-or D-biphenyl alanine, L- or D-3-benzotheinyl alanine, beta-alanine, L-or D- 2-pyridylalanine, L- or -D-3 -pyridylalanine, L- or D-4-pyridylalanine, L- or D-O, L -or D- O, iodophenylalanine, L- or D- 5-fluorotyrptophan, L- or D-tyrptophan, L- or D-tyrosine, L- or D-parachlorophenylalanine, L- or D-homophenylalnine, or L- or D-phenylglyine, L- or D-proline, or L- or D-valine.

[0126] The absolute configuration of hydrophilic and / or hydrophobic amino acids in each of AA2, AA3, and AA4 present in a compound o can vary. For example, in embodiments, each of AA2, AA3, and AA4 present in the compound can independently have any suitable combination of one or more of Agp, agp, R, r, HoArg, Hoarg, F, f, B, b, E, e, Nal, nal, Bip, bip, Bta, bta, K, k, V, v, Cit, cit, G, Y, y, W, w, P, p, 2-Pyr, 2-pyr, 3-Pyr, 3-pyr, Tyr(Ph), tyr(Ph), Phe(3-CN), phe(3-CN), Trp(5-F), trp(5-F), Phe(I), phe(l), Pepa, dPcpa, Hph, dHph, Phg, or dPhg residues (see Table 1 for amino acid abbreviations). For example, in embodiments, each of AA2, AA3, and AA4 present in the compound can each independently comprises Bip, F, R, Bta, Nal, RF, RK, FK, K-Bip, R-Bip, R-Bta, R- al, V-Cit, Agp-Bip, Agp-F, Cit-F, EF, FR, R-(2-Pyr), R-(3-Pyr), R-(4-Pyr), R-(Phe(I)), RG, RL, R(m)e-F(me), R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, R-Bta-B, KKKRK (SEQ ID NO: 13) KRKR (SEQ ID NO: 28), RF-B, RFR, RPF, RK- Nal, rk-Nal, FGR, (HoArg)-Bip, R-Bip-R, RFK, RGF, R-Nal-R, BRB-Bip (SEQ ID NO: 29), KRK-Nal (SEQ ID NO: 30), kkkr-Nal (SEQ ID NO: 31), KFKF (SEQ ID NO: 32), RFRF (SEQ ID NO: 33), KKRK-Nal (SEQ ID NO: 34), Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQID NO: 36), KKKRK-Nal (SEQ ID NO: 37), RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB ( SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF.

[0127] In embodiments, AA2 comprises Bip, F, R, Bta, Nal, RF, RK, FK, K-Bip, R-Bip, R-Bta, R-Nal, V-Cit, Agp-Bip, Agp-F Cit-F, EF, FR, R-(2-Pyr), R-(3-Pyr), R-(4-Pyr), R-(Phe(I)), RG, RL, R(me)-F(me), R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, R-Bta-B, KKKRK (SEQ ID NO: 13), KRKR (SEQ ID NO: 28), RF-B, RFR, RPF, RK-Nal, rk-Nal, FGR, (HoArg)-Bip, R-Bip-R, RFK, RGF, R-Nal-R, BRB-Bip (SEQ ID NO: 29), KRK-Nal (SEQ ID NO: 30), kkkr-Nal (SEQ ID NO: 31), KFKF (SEQ ID NO: 32), RFRF (SEQ ID NO: 33), KKRK-Nal (SEQ ID NO: 34), Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF.

[0128] In embodiments, AA3 comprises Bip, F, R, Bta, Nal, RF, RK, FK, K-Bip, R-Bip, R-Bta, R-Nal, V-Cit, Agp-Bip, Agp-F, Cit-F, EF, FR, R-(2-Pyr), R-(3-Pyr), R-(4-Pyr), R-(Phe(I)), RG, RL, R(me)-F(me), R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, R-Bta-B, KKKRK (SEQ ID NO: 13), KRKR (SEQ ID NO: 28), RF-B, RFR, RPF, RK-Nal, rk-Nal, FGR, (HoArg)- Bip, R-Bip-R, RFK, RGF, R-Nal-R, BRB-Bip (SEQ ID NO: 29), KRK-Nal (SEQ ID NO: 30), kkkr-Nal (SEQ ID NO: 31), KFKF (SEQ ID NO: 32), RFRF (SEQ ID NO: 33), KKRK-Nal (SEQ ID NO: 34), Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF.

[0129] In embodiments, AA4 comprises Bip, F, R, Bta, Nal, RF, RK, FK, K-Bip, R-Bip, R-Bta, KRKR, R-Nal, V-Cit, Agp-Bip, Agp-F, Cit-F, EF, FR, R-(2-Pyr), R-(3-Pyr), R-(4-Pyr), R- (Phe(I)), RG, RL, R(me)-F(me), R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, R- Bta-B, KKKRK (SEQ ID NO: 13), KRKR (SEQ ID NO: 28), RF-B, RFR, RPF, RK-Nal, rk-Nal, FGR, (HoArg)-Bip, R-Bip-R, RFK, RGF, R-Nal-R, BRB-Bip (SEQ ID NO: 29), KRK-Nal (SEQ ID NO: 30), kkkr-Nal (SEQ ID NO: 31), KFKF (SEQ ID NO: 32), RFRF (SEQ ID NO: 33), KKRK-Nal (SEQ ID NO: 34), Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), FRF.

[0130] In embodiments, each of AA2, AA3, and AA4 present in the compound of is independently selected from one of the following groups:(Group A) KKKRK (SEQ ID NO: 13), RK, RF, or R;(Group B) Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 30), KKRK-Nal (SEQ ID NO: 34), KRK-Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, V-Cit, Cit-R, EF, FGR, FR, (HoArg)-Bip, KRKR (SEQ ID NO: 28), R-(2-Pyr), R-(3-Pyr), R(4-Pyr), R-Bip-R, R-(Phe(I)), RFK, RFRF (SEQ ID NO: 33), RG, RGF, RL, R(me)-F(me), R-Nal-R, R-(Phe(3-CN)), R-(Trp(5-F), R- (Tyr(Ph), RW, RY, SF, RPF, Agp-Bip, Agp-F, RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF; and(Group C) Bip, F, R, Bta, Nal, RF, or F.

[0131] In embodiments, AA2 comprises KKKRK (SEQ ID NO: 13), RK, orRF. In embodiments, AA2 comprises KKKRK (SEQ ID NO: 13). In embodiments, AA2 comprises RK. In embodiments, AA2 comprises KKKRK (SEQ ID NO: 13). In embodiments, AA2 comprises RF. In embodiments, AA2 comprises R.

[0132] In embodiments, AA3 comprises Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 34), KKRK-Nal (SEQ ID NO: 34), KRK-Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, or V-Cit. In embodiments, AA3 comprises Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 34), KRK-Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, V-Cit, Cit-R, EF, FGR, FR, (HoArg)-Bip, KRKR (SEQ ID NO: 28), R-(2-Pyr), R-(3-Pyr), R(4-Pyr), R-Bip-R, R-(Phe(l)), RFK, RFRF (SEQ ID NO: 33), RG, RGF, RL, R(me)-F(me), R-Nal-R, R-(Phe(3-CN)), R-(Trp(5-F), R-(Tyr(Ph), RW, RY, SF, RPF, Agp-Bip, Agp-F, RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF.

[0133] In embodiments, AA3 comprises Bip-BRBRB (SEQ ID NO: 35). In embodiments, AA3 comprises Nal-BRBRB (SEQ ID NO: 36). In embodiments, AA3 comprises KKKRK-Nal (SEQ ID NO: 37). In embodiments, AA3 comprises BRB-Bip (SEQ ID NO: 29). In embodiments, AA3 comprises FK. In embodiments, AA3 comprises K-Bip. In embodiments, AA3 comprises kkkr-Nal (SEQ ID NO: 31). In embodiments, AA3 comprises KKRK-Nal (SEQ ID NO: 34). Inembodiments, AA3 comprises KRK-Nal (SEQ ID NO: 30). In embodiments, AA3 comprises Nal. In embodiments, AA3 comprises R-Bip. In embodiments, AA3 comprises R-Bta. In embodiments, AA3 comprises R-Bta-B. In embodiments, AA3 comprises RF-B. In embodiments, AA3 comprises RFR. In embodiments, AA3 comprises RK-Nal. In embodiments, AA3 comprises rk-Nal. In embodiments, AA3 comprises R-Nal. In embodiments, AA3 comprises V-Cit. In embodiments, AA3 comprises Cit-R. In embodiments, AA3 comprises EF. In embodiments, AA3 comprises FGR. In embodiments, AA3 comprises FR. In embodiments, AA3 comprises (HoArg)-Bip. In embodiments, AA3 comprises KRKR (SEQ ID NO: 28). In embodiments, AA3 comprises R-(2-Pyr). In embodiments, AA3 comprises R-(3-Pyr). In embodiments, AA3 comprises R-(4-Pyr). In embodiments, AA3 comprises R-Bip-R. In embodiments, AA3 comprises R-(Phe(I)). In embodiments, AA3 comprises RFK. In embodiments, AA3 comprises RFRF (SEQ ID NO: 33). In embodiments, AA3 comprises RG. In embodiments, AA3 comprises RGF. In embodiments, AA3 comprises RL. In embodiments, AA3 comprises R(me)-F(me). In embodiments, AA3 comprises R-Nal-R. In embodiments, AA3 comprises R-(Phe(3-CN)). In embodiments, AA3 comprises R-(Trp(5-F)). In embodiments, AA3 comprises R-(Tyr(Ph)). In embodiments, AA3 comprises RW. In embodiments, AA3 comprises RY. In embodiments, AA3 comprises SF. In embodiments, AA3 comprises Agp-Bip. In embodiments, AA3 comprises RPF. In embodiments, AA3 comprises Agp-F. In embodiments, AA3 comprises RFE. In embodiments, AA3 comprises R-(Phg). In embodiments, AA3 comprises R-(Hph). In embodiments, AA3 comprises (Pcpa)-F. In embodiments, AA3 comprises R-(Hph). In embodiments, AA3 comprises BR-Bip-RB (SEQ ID NO: 85). In embodiments, AA3 comprises RRFF (SEQ ID NO: 86), In embodiments, AA3 comprises FRF.

[0134] In embodiments, AA4 comprises Bip, F, R, Bta, or Nal. In embodiments, AA4 comprises Bip. In embodiments, AA4 comprises F. In embodiments, AA4 comprises R. In embodiments, AA4 comprises Bta. In embodiments, AA4 comprises Nal In embodiments, AA4 comprises RF In embodiments, AA4 comprises F.

[0135] In embodiments where a2 is 0, a3 is 1, and a4 is 0, AA3 comprises Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, Agp-F, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 34), KRK- Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, V-Cit, Cit-R, EF, FGR, FR, (HoArg)-Bip, KRKR (SEQ ID NO: 28), R-(2-Pyr), R-(3-Pyr), R(4-Pyr), R-Bip-R, R-(Phe(T)), RFK, RFRF (SEQ ID NO: 33), RG, RGF, RL, (Rme)-(Fme), R-Nal-R, R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, RPF, Agp-Bip, RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF.

[0136] In embodiments where a2 is 0, a3 is 1, and a4 is 1, AA3 comprises Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, Agp-F, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 34), KRK-Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, V-Cit, Cit-R, EF, FGR, FR, (HoArg)-Bip, KRKR (SEQ ID NO: 28), R-(2-Pyr), R-(3-Pyr), R(4-Pyr), R-Bip-R, R-(Phe(I)), RFK, RFRF (SEQ ID NO: 33), RG, RGF, RL, (Rme)-(Fme), R-Nal-R, R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, RPF, Agp-Bip, RPF, Agp-Bip, RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF, and AA4 comprises Bip, F, R, Bta, Nal, RF, or F.

[0137] In embodiments where a2 is 1, a3 is 0, and a4 is 0, AA2 comprises KKKRK (SEQ ID NO: 13), RK, orRF.

[0138] In embodiments where a2 is 1, a3 is 1, and a4 is 0, AA2 comprises KKKRK, RK, RF, or R and AA3 comprises Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, Agp-F, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 34), KRK-Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, V-Cit, Cit-R, EF, FGR, FR, (HoArg)-Bip, KRKR (SEQ ID NO: 28), R-(2-Pyr), R-(3-Pyr), R(4-Pyr), R-Bip-R, R-(Phe(I)), RFK, RFRF (SEQ ID NO: 33), RG, RGF, RL, R(me)-F(me), R-Nal-R, R-(Phe(3-CN)), R-(Trp(5-F), R-(Tyr(Ph), RW, RY, SF, RPF, Agp-Bip, RPF, Agp-Bip, RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF.

[0139] In embodiments where AA3 and AA4 are present, AA3 comprises Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), BRB-Bip (SEQ ID NO: 29), FK, K-Bip, Agp-F, kkkr-Nal (SEQ ID NO: 31), KKRK-Nal (SEQ ID NO: 34), KRK- Nal (SEQ ID NO: 30), Nal, R-Bip, R-Bta, R-Bta-B, RF-B, RFR, RK-Nal, rk-Nal, R-Nal, V-Cit, Cit-R, EF, FGR, FR, (HoArg)-Bip, KRKR (SEQ ID NO: 28), R-(2-Pyr), R-(3-Pyr), R(4-Pyr), R- Bip-R, R-(Phe(I)), RFK, RFRF (SEQ ID NO: 33), RG, RGF, RL, (Rme)-(Fme), R-Nal-R, R- (Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, RPF, Agp-Bip, RPF, Agp-Bip, RFE, R-(Phg), R-(Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), or FRF; and AA4 comprises Bip, F, R, Bta, or Nal.

[0140] In embodiments, only one of AA2, AA3, and AA4 is present in the compound (e.g., only 1 of a2, a3, and a4 is 1) and is a single hydrophilic amino acid residue. In embodiments of, a2 is 1, a3 is 0, a4 is 0, and AA2 is a single hydrophilic amino acid residue. In embodiments of, single hydrophilic amino acid residue has an aromatic side chain. In embodiments of, the single hydrophilic amino acid residue is D- or L-naphthylalanine or D- or L-biphenylalanine.

[0141] In embodiments, two of AA2, AA3, and AA4 are present in the compound (e.g., 2 of a2, a3, and a.4 are 1) and each of the two AA2, AA3, and AA4 groups present in the compound independently consist of a single hydrophilic amino acid residue. In embodiments, a2 is 1, a3 is 1, a4 is 0, and AA2 and AA3 consist of a single hydrophilic amino acid residue. In embodiments, each of the two single hydrophilic amino acids independently have an aromatic side chain In embodiments, the two single hydrophilic amino acid residues are each independently D- or L-naphthylalanine orD- or L-biphenylalanine.cCPP (cyclic Cell Penetrating Peptide): R1, R2, R3, R4, R5, R6, and R7

[0142] The delivery constructs and therefore compounds that include a delivery construct include a cyclic cell penetrating peptide (cCPP). The cCPP is formed from a cCPP bridging amino acid residue and the amino acid residues characterized by the R1, R2, R3, R4, R5, R6, and R7side chains. As such, R1, R2, R3, R4, R5, R6, and R7are each independently the side chain of an amino acid. The cCPP bridging amino acid residue is the amino acid residue connecting the amino acid residue characterized by the R1side chain and the amino acid residue characterized by the R7side chain. The cCPP is designed to facilitate cell membrane penetration of the compound to which it is attached.

[0143] The side chain of the cCPP bridging amino acid residue is covalently attached to the side chain of an exocyclic bridging amino acid residue. The exocyclic bridging amino acid residue is the amino acid residue that has a side chain covalently attached to the cCPP. For example, the coupling between the side chain of the cCPP bridging amino acid residue and the exocyclicbridging amino acid residue can be visualized as compound) where the cCPP bridging amino acid residue is shown as connected to the cCPP (the partial circle), the exocyclic bridging amino acid residue is the amino acid residue having a backbone that is not within the cCPP (the carbonyl is not a part of the cCPP), n is integer from 0 to 3, and y is an integer from 1 to 5. The cCPP bridging amino acid residue can be characterized by n. The exocyclic bridging amino acid residue can be characterized by y. n can be 0 n can be 2. n can be 3. When n is 0, the bridging cCPP amino acid residue is asparagine. When n is 1, the bridging cCPP amino acid residue is glutamine, y can be 1 y can be 2. y can be 3. y can be 4. y can be 5. When y is 4, the exocyclic bridging amino acid residue is lysine. In embodiments the bridging cCPP amino acid residue is glutamine (n is 1) and the bridging exocyclic amino acid residue is lysine (y is 4).

[0144] A cCPP connected to the larger compound can be denoted as JA(cyclo[XAXBXcXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with the side chains R1, R2, R3, R4, R3, R6, and R7, respectively; YAis the cCPP bridging amino acid residue, and JAis the exocyclic bridging amino acid residue. For example, XAis the amino acid residue having the side chain of R1, XBis the amino acid residue having the side chain of R2, XCis the amino acid residue having the side chain of R3, XDis the amino acid residue having the side chain of R4, XEis the amino acid residue having the side chain of R5, XFis the amino acid residue having the side chain of R6, and XGis the amino acid residue having the side chain of R7. In embodiments where JAis L-or D-lysine (K or k) and YAis L-or D-glutamine (Q or q),the cCPP can be denoted as K / k(cyclo[XAXBXcXDXEXFXGQ / q]).

[0145] In embodiments, though not shown in some Formulea, the amide nitrogen of an amino acid residue in a cCPP can be methylated (-CH3). Such amino acid residues can be described as the N-m ethylated amino acid name or amino acid shorthand followed by (N-me). For example,the cCPP can include N-methylated phenylalanine ((F(N-me), f(N-me))) or N-methylated glycine (G(N-me)).

[0146] R1, R2, R3, R4, R5, R6, and R7can be any combination of amino acid side chains. Similar to the AA2, AA3, and AA4 groups, the combination of hydrophilic and hydrophobic amino acid residues in the cCPP can influence the efficacy of the compound.

[0147] In embodiments, at least 2 of R1, R2, R3, R4, R5, R6, and R' are the side chain of a hydrophobic amino acid residue. In embodiments, at least 3 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue. In embodiments, at least 4 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue. In embodiments, at least 4 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue. In embodiments, 2 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue. In embodiments, 3 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue. In embodiments, 4 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue. In embodiments, 5 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue.

[0148] In embodiments, at least 2 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophilic amino acid residue. In embodiments, at least 3 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophilic amino acid residue. In embodiments, at least 4 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophilic amino acid residue. In embodiments, 2 of R1, R2, R3, R4, R3, R6, and R7are the side chain of a hydrophilic amino acid residue. In embodiments, 3 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophilic amino acid residue. In embodiments, 4 of R1, R2, R3, R4, R3, R6, and R7are the side chain of a hydrophilic amino acid residue.

[0149] In embodiments 3 of R1, R2, R’, R4, R3, R6, and R7are the side chain of a hydrophobic amino acid residue and 4 of R1, R2, R3, R4, R3, R6, and R7are the side chain of a hydrophilic amino acid residue.

[0150] In embodiments 4 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue and 3 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophilic amino acid residue.

[0151] In embodiments 5 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophobic amino acid residue and 2 of R1, R2, R3, R4, R5, R6, and R7are the side chain of a hydrophilic amino acid residue.

[0152] In embodiments, for each R1, R2, R3, R4, R5, R6, and R7that is the side chain of a hydrophobic amino acid residue, the hydrophobic amino acid residue can be an aromatic amino acid residue; an uncharged, not aromatic, hydrocarbon amino acid residue; or an amino acid residue having no side chain. In embodiments, each aromatic amino acid of the cCPP is independently selected from L- or D-phenylalanine, L- or D-naphthylalanine, L- or D-3-benzotheinyl alanine, or L-or D-biphenylalanine. In embodiments, each uncharged, not aromatic, hydrocarbon amino acid residue of the cCPP is independently selected from L- or D-valine or L-or-D leucine. In embodiments, each hydrophobic amino acid residue in the cCPP that has no side chain is glycine.

[0153] In embodiments, for each R1, R2, R3, R4, R5, R6, and R7that is the side chain of a hydrophobic amino acid residue, the hydrophobic amino acid residue can be an aromatic amino acid residue; an uncharged, not aromatic, hydrocarbon amino acid residue; or an amino acid residue having no side chain. In embodiments, each aromatic amino acid of the cCPP is independently selected from L- or D-phenylalanine, L- or D-naphthylalanine, L- or D-3- benzotheinyl alanine, L-or D-biphenylalanine, L- or D-tyrosine, L-or D-2-pyridylalanine, L- orD-4-pyridylalanine, L-or D- O, iodophenylalanine, L- or D- 5-fluorotyrptophan, or L- or D-para-chlorophenylalanine. In embodiments, when one of R1, R2, R3, R4, R5, R6, and R7is the side chain of phenylalanine, the amino acid is N-methylated phenylalanine. In embodiments, each uncharged, not aromatic, hydrocarbon amino acid residue of the cCPP is independently selected from L- or D-valine, L- or-D leucine, or L- or D-alanine. In embodiments, each hydrophobic amino acid residue in the cCPP that has no side chain is glycine.

[0154] In embodiments, for each R1, R2, R3, R4, R5, R6, and R7that is the side chain of a hydrophilic amino acid, the hydrophilic amino acid can be a charged amino acid residue. Inembodiments, each charged amino acid in the cCPP is independently selected from L- or D-arginine or L- or D-histidine.

[0155] In embodiments, for each R1, R2, R3, R4, R5, R6, and R7that is the side chain of a hydrophilic amino acid, the hydrophilic amino acid can be a charged amino acid residue. In embodiments, each charged amino acid in the cCPP is independently selected from L- or D-Y o arginine, L- or D-histidine, L- or D-, L- or D- or L- or D-citrulline.

[0156] In embodiments, for each R1, R2, R3, R4, R5, R6, and R7that is the side chain of a hydrophilic amino acid, the hydrophilic amino acid can be a charged amino acid residue. In embodiments, each, uncharged, not aromatic, hydrocarbon amino acid residue of the cCPP is independently selected from L- or D-valine, L- or-D leucine, or L- or D-alanine.

[0157] In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid residue;R5and R7are each independently a side chain of a hydrophilic amino acid residue; andR4and R6are each independently a side chain of a hydrophobic amino acid or the side chain of a hydrophilic amino acid residue.In embodiments,R1, R2, and R are each independently a side chain of a hydrophobic amino acid residue where at least two of R1, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine or L- or D-3-benzotheinyl alanine;R5and R7are each independently a side chain of a charged amino acid residue, optionally selected from the side chain of L- or D-arginine, L- or D-citrulline, or L- or D-histidine; and R4and R6are each independently a side chain of a hydrophobic amino acid residue or a side chain of a hydrophilic amino acid residue.

[0158] In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid residue where at least two of R1, R2, and R3are each independently an aromatic amino acid side chain optionallyselected from the side chain of L- or D-phenylalanine, L- or D-naphthyl alanine, L- or D-3-benzotheinyl alanine, L-or D-biphenylalanine, L- or D-tyrosine, L-or D-2-pyridylalanine, L- or CN< CM, OH X OHY H2N' YD-4-pyridylalanine, L-or D- O, O, iodophenylalanine, L- or D-5-fluorotyrptophan, or L- or D-parachlorophenylalanine;R5and R7are each independently a side chain of a charged amino acid residue, optionallyselected from the side chain of L- or D-arginine, L- or D-citrulline, L- or D-, L- orD-O, or L- or D-histidine, andR4and R6are each independently a side chain of a hydrophobic amino acid residue or a side chain of a hydrophilic amino acid residue.

[0159] In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid residue where two of R1, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine or L- or D-3-benzotheinyl alanine and where one of R1, R2, and R3is H;R5and R7are each independently a side chain of a charged amino acid, optionally selected from the side chain of L- or D-arginine, L- or D-citrulline, or L- or D-histidine; andR4and R6are each independently a side chain of a hydrophobic amino acid or a side chain of a hydrophilic amino acid.

[0160] In embodiments,R1, R2, and R are each independently a side chain of a hydrophobic amino acid residue where two of R1, R2, and R3are each independently an aromatic amino acid side chain optionally selected from L- or D-phenylalanine, L- or D-naphthylalanine, L- or D-3-benzotheinyl alanine,r CH A,. OH H2N' Y L-or D-biphenylalanine, L- or D-tyrosine, L- or D-4-pyridylalanine, L-or D- O CNA OHH2N' YL- or D- O L- or D-iodophenylalanine, L- or D- 5 -fluor otyrp tophan, or L- or D-parachlorophenylalanine, and where one of R1, R2, and R3is H;R5and R7are each independently a side chain of a charged amino acid, optionally selected from NH2X OHH2W' Y the side chain of L- or D-arginine. L- or D-citrulline, L- or D-, L- or D-6, or L- or D-histidine; andR4and R6are each independently a side chain of a hydrophobic amino acid or a side chain of a hydrophilic amino acid.

[0161] In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid where at least two of R1, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine or L- or D-3-benzotheinyl alanine;R5and R7are each independently a side chain of a charged amino acid, optionally selected from the side chain of L- or D-arginine, L- or D-citrulline, or L- or D-histidine; andR4and R6are each independently a side chain of a charged hydrophilic amino acid optionally selected from L-or D-arginine, L-or D-citrulline, or L-or D-histidine.[01621 In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid where at least two of R’, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine or L- or D-3-benzotheinyl alanine;R5and R7are each independently a side chain of a charged amino acid, optionally selected from the side chain of L- or D-arginine, L- or D-citrulline, or L- or D-histidine; andR4and Rbare each independently H or a side chain of a hydrophobic amino acid having a hydrocarbon side chain and no aromatic group, the hydrophobic amino acid optionally selected from L- or D-valine or L-or D-leucine.

[0163] In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid where at least two of R1, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine or L- or D-3-benzotheinyl alanine;R5and R7are each independently a side chain of a charged amino acid, optionally selected from the side chain of L- or D-arginine, L- or D-citrulline, or L- or D-histidine; andR4and Rbare each H.

[0164] In embodiments,R1, R2, and R3are each independently a side chain of a hydrophobic amino acid where at least two of Rf, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine, L- or D-3-benzotheinyl alanine, L- or D-£1r CM A „OHH2N Y naphthylalanine, L- or D-4-pyridyl alanine, L - or D-tyrosine, L-or D- O, L- or CND- O, or L- or D-parachlorophenylalanine;R5and R7are each independently a side chain of a charged amino acid, optionally selected from HH2the side chain of L- or D-arginine, L- or D-citrulline, L- or D-, L- or D-HHu wA.0, or L- or D-histidine; andR4and R6are each H.

[0165] In embodiments,R1, R, and R3are each independently a side chain of a hydrophobic amino acid;at least two of R1, R2, and R3are each independently an aromatic amino acid side chain optionally selected from the side chain of L- or D- valine, L- or-D leucine, or L- or D-alanine; one of R1, R2, and R3is H, and one of R1, R2, and R is an aromatic amino acid side chain optionally selected from the side chain of L- or D-phenylalanine;R5and R7are each independently a side chain of a charged amino acid, optionally selected from NH2HN J‘. " NHX OHo the side chain of L- or D-arginine, L- or D-citrulline, L- or D-, L- or D- HyN,, NH0, or L- or D-histidine; andR4and R6are each H.

[0166] In embodiments,R1is H or a side chain or an aromantic amino acid optionally selected from L- or D-phenylalanine or L- or D-3-benzotheinyl alanine;R2is H or a side chain or an aromantic amino acid optionally selected from L- or D-phenylalanine orL- or D-3-benzotheinyl alanine;R1is a side chain of an aromatic amino acid optionally selected from optionally selected from L-or D-phenylalanine or L- or D-3-benzotheinyl alanine;R4is H or a side chain of a non-aromatic amino acid optionally selected from L- or D-valine, L-or D-leucine, or L- or D-arginine;R3is a side chain of a charged amino acid optionally selected from D- or L-arginine or L- or D-histidine;R” is H or ta side chain of a non-aromatic amino acid optionally selected from L- or D-valine, Ivor D-leucine, or L- or D-arginine; andR7is a side chain of a charged amino acid optionally selected from D- or L-arginine or L- or D-histidine.

[0167] In embodiments,R1, R3, R’, and R ' are each independently a H or a side chain of a hydrophobic amino acid residue; andR2, R4, and R6are each independently a side chain of hydrophilic amino acid residue.[016S] In embodiments,R1, R3, R5, and R7are each independently H or a side chain of a hydrophobic amino acid residue optionally selected from D- or L-phenyl lanine; andR2, R4, and R6re each independently a side chain of hydrophilic amino acid residue optionally selected from D- or L-arginine.

[0169] In embodiments,R1, R2, R4, R5, and R7are each independently I I or a side chain of a hydrophobic amino acid residue; andR3and Rbare each independently a side chain of hydrophilic amino acid residue,

[0170] In embodiments,R1, R2, R4, R', and R7are each independently H or a side chain of a hydrophobic amino acid residue optionally selected from D- or L-phenylalanine; andRJand R6are each independently a side chain of hydrophilic amino acid residue optionally selected from D- or L-arginine.

[0171] In embodiments,R1is H or the side chain of L- or D-3-benzotheinyl alanine or L- or D-phenylalanine;R2is H or the side chain of L- or D-3-benzotheinyl alanine or L- or D-phenylalanine;RJis H or the side chain of L- or D-3-benzotheinyl alanine or L- or D-phenylalanine;R4is H or the side chain of L- or D-leucine, L- or D-valine, L- or D-histidine, and L- or D-arginine;R3is the side chain of L- or D-arginine or L- or D-histidine;R6is H or the side chain L- or D-leucine, L- or D-valine, L- or D-histidine, or L- or D-arginine; andR7is the side chain or L- or D-arginine or L- or D-histidine.

[0172] In embodiments.R1is H or the side chain of L- or D-3-benzotheinyl alanine, L- or D-phenylalanine, L- or D-4-pyridylalanine, L- or D-alanine, L- or D- O, L- or D- Q, or Lor D-parachlorophenylalanine;R2is H or the side chain of L- or D-3-benzotheinyl alanine, L- or D-tyrosine, L- or D-alanine, or L- or D-phenylalanine;RJis H or the side chain of L- or D-3-benzotheinyl alanine, L- or D-phenylalanine, L- or D-f " CN A, OH H2N Y tyrosine, L- or D-4-pyridylalanine, L- or D-alanine, L- or D- O,. L- or D- GNA. OHH2N hfb, or L- or D-parachlorophenylalanine;R4is H or the side chain of L- or D-leucine, L- or D-valine, L- or D-histidine, and L- or D-arginine;R5is the side chain of L- or D-arginine, L- or D-histidine, c L- or D-citrulline, L- or D-NH, OH®; or L- or D- 0;R6is H or the side chain of L- or D-leucine, L- or D-valine, L- or D-histidine, or L- or D-arginine; andR7is the side chain or L- or D-arginine. L- or D-histidine, L- or D-citrulline, L- or D-z'OHO; or L- or D-

[0173] In embodiments,R1is H or the side chain of L- or D-3-benzotheinyl alanine or L- or D-phenylalanine;R2is H or the side chain of L- or D-phenylalanine;RJis the side chain of L- or D-3-benzotheinyl alanine or L- or D-phenylalanine;R4is H or the side chain of L- or D-leucine, L- or D-arginine, or L- or D-valine;R5is the side chain of L- or D-arginine or L- or D-histidine,R6is H or the side chain of L- or D-leucine, L- or D-valine, or L- or D-arginine; andR7is the side chain or L- or D-arginine or L- or D-histidine.

[0174] In embodiments,R1is II or the side chain of I - or D-3-benzotheinyl alanine, phenyl lanine, L- or D-4-pyridylalanine, L- or D-alanine, L- or D- 6 or D-parachlorophenylalanine;R2is H or the side chain of L- or D-3-benzotheinyl alanine, L- or D-alanine, L- or D-phenyl alanine, L- or D-arginine, L- or D-tyrosine, or L- or D-arginine;R3is H or the side chain of L- or D-3-benzotheinyl alanine, L- or D-alanine, L- or D-phenylalanine, L- or D-4-pyridylalanine, L- or D-alanine, L- or D-tyrosine, L- or D- CNE 'CM y ■<-'A OH A OHH2N' y H2N'naphthylalanine, L- or D- O, L- or D- O, L- or D-parachlorophenylalanine, or L- or D-arginine;R4is H or the side chain of L- or D-leucine, L- or D-valine, L- or D-histidine, and L- or D argmine;R? is the side chain of L- or D-arginine, L- or D-histidine, L- or D-citrulline, L- or DNH2, NH. AHN NH„NHA y OH.. OHH2No, L- or D- 0, or L- or D-phenylalanine;R6is H or the side chain of L- or D-leucine, L- or D-valine, L- or D-histidine, or L- or D-arginine; andR7is II or the side chain, L- or D-arginine, L- or D-histidine, L- or D-citrulline, L- or D- NHgHH'MH,. NHOHH2Mo T rx, or L- or D- O

[0175] In embodiments, R5and R ' are the side chain of arginine, R4and Rbare H or an amino acid side chain and two of R1, R, and R3, are, independently the side chain of phenylalanine and one of R3, R2, and R3is H or R1, R2, and R3are the side chain of phenylalanine.

[0176] In embodiments, the cCPP can have the sequence cyclo[Bta-G-Bta-GRGRQ] (SEQ ID NO: 38), cyclo[FfFGRGRQ] (SEQ ID NO: 39), cyclo[FGFGRGRQ] (SEQ ID NO: 40), cyclofFGFLRLRQ] (SEQ ID NO: 41), cyclofFGFRHRHQ] (SEQ ID NO: 42),cyclofFGFVRVRQ] (SEQ ID NO: 43), cyclofGfFGrGrQ] (SEQ ID NO: 44), cycloffGfrrrrQ] (SEQ ID NO: 45), cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ] (SEQ ID NO: 46), cyclofAGFGRGRQ] (SEQ ID NO: 47), cyclofFFFGRGRQ] (SEQ ID NO: 48), cyclofFFGRRGQ] (SEQ ID NO: 49), cyclo[FGAGRGRQ] (SEQ ID NO: 50), cyclo[FGFG-Cit-GRQ] (SEQ ID NO: 51), cyclo[FGFGRG-Cit-Q] (SEQ ID NO: 52), cyclo[FGFGRrRQ] (SEQ ID NO: 53), cyclofFRFRFRFQ] (SEQ ID NO: 54), cyclo[G-f(N-me)-FGrGrQ] (SEQ ID NO: 55), cyclo[Gf-Nal-GrGrQ] (SEQ ID NO: 56), cyclofGFRGFRGQ] (SEQ ID NO: 57), cyclo[Gv YGrGrQ] (SEQ ID NO: 58), and cyclo[(Phe(4-CN))-G-(Phe(4-CN))-GRGRQ] (SEQ ID NO: 59), cyclofFGF-G(N-me)-RGRQ] (SEQ ID NO: 60), cyclo[F-G(N-me)-FGRGRQ] (SEQ ID NO: 61), cyclofFAFARGRQ] (SEQ ID NO: 62), cyclo[FGFG-Agp-G-Agp-Q] (SEQ ID NO: 63), cyclo[(Pcpa)-G-(Pcpa)-GRGRQ] (SEQ ID NO: 64), cyclofGFFGRGRQ] (SEQ ID NO: 65), cyclo[GRFGRFGQ] (SEQ ID NO: 66), cyclofRFGGRFGQ] (SEQ ID NO: 67), cyclofFGFRRRRQ] (SEQ ID NO: 81), cycloffffrrrrQ] (SEQ ID NO: 82), cycloffGfGrGrQ] (SEQ ID NO: 83), or cyclofFGRGFGRQ] (SEQ ID NO: 84), where Q is the cCPP bridging amino acid. In embodiments, the cCPP has the sequence cyclo[Bta-G-Bta-GRGRQ] (SEQ ID NO: 38). In embodiments, the cCPP has the sequence cyclo[FfFGRGRQ] (SEQ ID NO: 39). In embodiments, the cCPP has the sequence cyclo[FGFGRGRQ] (SEQ ID NO: 40). In embodiments, the cCPP has the sequence cyclo[FGFLRLRQ] (SEQ ID NO: 41). In embodiments, the cCPP has the sequence cyclofFGFRHRHQ] (SEQ ID NO: 42). In embodiments, the cCPP has the sequence cyclofFGFVRVRQ] (SEQ ID NO. 43). In embodiments, the cCPP has the sequence cyclofGfFGrGrQ] (SEQ ID NO: 44). In embodiments, the cCPP has the sequence cycloffGfrrrrQ] (SEQ ID NO: 45). In embodiments, the cCPP has the sequence cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ] (SEQ ID NO: 46). In embodiments, the cCPP has the sequence cyclofAGFGRGRQ] (SEQ ID NO: 47). In embodiments, the cCPP has the sequence cyclo[FFFGRGRQ] (SEQ ID NO: 48). In embodiments, the cCPP has the sequence cyclofFFGRRGQ] (SEQ ID NO: 49). In embodiments, the cCPP has the sequence cyclofFGAGRGRQ] (SEQ ID NO: 50). In embodiments, the cCPP has the sequence cyclo[FGFG-Cit-GRQ] (SEQ ID NO: 51). In embodiments, the cCPP has the sequence cyclofFGFGRG-Cit-Q] (SEQ ID NO: 52). In embodiments, the cCPP has the sequence cyclofFGFGRrRQ] (SEQ ID NO: 53). In embodiments, the cCPP has the sequence cyclofFRFRFRFQ] (SEQ ID NO: 54). In embodiments, the cCPP has the sequence cyclo[G-f(N-me)-FGrGrQ] (SEQ ID NO: 55). Tn embodiments, the cCPP has the sequence cyclo[Gf-Nal-GrGrQ] (SEQ ID NO: 56), In embodiments, the cCPP has the sequence cyclo[GFRGFRGQ] (SEQ ID NO: 57). In embodiments, the cCPP has the sequence cyclo[GyYGrGrQ] (SEQ ID NO: 58). In embodiments, the cCPP has the sequence cyclo[(Phe(4-CN))-G-(Phe(4-CN))-GRGRQ] (SEQ ID NO: 59). In embodiments, the cCPP has the sequence cyclo[FGF-G(N-me)-RGRQ] (SEQ ID NO: 60). In embodiments, the cCPP has the sequence cyclo[F-G(N-me)-FGRGRQ] (SEQ ID NO: 61). In embodiments, the cCPP has the sequence cyclo[FAFARGRQ] (SEQ ID NO: 62). In embodiments, the cCPP has the sequence cyclo[FGFG-Agp-G-Agp-Q] (SEQ ID NO: 63). In embodiments, the cCPP has the sequence cyclo[(Pcpa)-G-(Pcpa)-GRGRQ] (SEQ ID NO: 64). In embodiments, the cCPP has the sequence cyclo[GFFGRGRQ] (SEQ ID NO: 65). In embodiments, the cCPP has the sequence cyclofGRFGRFGQ] (SEQ ID NO: 66). In embodiments, the cCPP has the sequence cyclo[RFGGRFGQ] (SEQ ID NO: 67). In embodiments, the cCPP has the sequence cyclo[FGFRRRRQ] (SEQ ID NO: 81). In embodiments, the cCPP has the sequence cyclo[fffrrrrQ] (SEQ ID NO: 82). In embodiments, the cCPP has the sequence cycloffGfGrGrQ] (SEQ ID NO: 82). In embodiments, the cCPP has the sequence cyclo[FGRGFGRQ] (SEQ ID NO: 84).Coupling Group: M'

[0177] A compound including a delivery constaict can include a terminal reactive handle that reacts with a complementary reactive handle on the cargo to form the delivery construct-cargo conjugate. In embodiments, post conjugation, the cargo is directly coupled to the delivery construct. In other embodiments, post conjugation, the cargo is coupled to the delivery construct through a coupling group M'. In embodiments when M' is present in the compound, M' can include at least a portion of the reaction product of the two reactive handles and, optionally, one or more additional atoms or groups.

[0178] ml can be 0 or 1. In embodiments, ml is 0. In embodiments ml is 1.

[0179] When ml is 0, the delivery construct is directly attached to the cargo. For example, in embodiments when the cargo is a PMO and ml is 0, the delivery construct is covalently bonded to the free secondary amine of the morpholino ring of the 3' terminal end of a PMO, For example, in embodiments when ml is 0 and the cargo is a PMO, the connection between the,.o.vJ1PMO cargo and the delivery construct canbe ** where B is the 3' terminal nucleobase of the PMO cargo, * indicates the point of attachment to the remaining PMO cargo, and ** indicates the point of attachment to delivery construct.

[0180] In embodiments when the cargo is a PNA and ml is 0, the delivery construct can be covalently bonded to the free amine of the N-terminus of a PNA. For example, in embodiment when ml is 0 and the cargo is a PNA, the connection between the PNA cargo and the deliveryNHL— Xconstruct can beO?'** where Bnis the N-terminal nucleobase of the PNA cargo, * indicates the point of attachment to the remaining PNA cargo, and ** indicates the point of attachment to delivery construct.

[0181] In embodiments when ml is 1, the compound comprises M'. In embodiments, when ml is 1, the cargo is coupled to the larger delivery construct through M7.

[0182] M' can be covalently bound to any suitable location on the cargo. For example, M' can be covalently bound to the 3’ end or 5' end of an ASO cargo.oJU

[0183] M' can include -NH-, 'M t' 5 ‘, or a heteroaryl where t is an integer from 0 to 10. t can be an integer from 0 to 5. t can be an integer from 0 to 3.

[0184] In embodiments, M' is a bond to the cargo.

[0185] In embodiments, M' can include or be -Nil- O

[0186] In embodiments, M' can includeor be where t is an integer from 0 to 5.

[0187] In embodiments, M' can include a heteroaryl. The heteroaryl may include the reaction product between an azide and cyclooctyne. For example, M' can be or includethereof where y" is an integer from 1 to 4, In embodiment when y” is 4, the heteroaryl containing group is the reaction product between azidolysine and cyclooctyne.

[0188] M' can be covalently bound to 3' end or the 5' end of the ASO cargo. In embodiments M' is covalently bound to the 3' end of the ASO cargo. In embodiments M' is covalently bound to the 5' end of the ASO cargo. In embodiments where the cargo is a PMO, M' can form a bond to the free hydroxyl of the of the 5' terminal nucleotide of an PMO.

[0189] In embodiments when the cargo is a PMO, M' is a bond to the free secondary' amine of the morpholino ring of the 3' terminal nucleotide of the PMO.

[0190] In embodiments, the M' may include a heteroaryl and one or more -CH2CH2O- units. For example, in embodiments, M' can include or bewhere #1 is the M' point of attachment to the delivery construct, #2 is the point of attachment to the cargo, y" is an integer from 1 to 4, x3 is an integer from 1 to 4, and j3 is an integer from 1 to 4. In embodiment when y" is 4, the heteroaryl containing group is the reaction product between azidolysine and cyclooctyne. In embodiments, x3 is 2. In embodiments, x3 is 4. In embodiments, j3 is 1. Tn embodiments, j 3 is 2. In embodiments, j 3 is 3. In embodiments, j is 4. In embodiments, y" is 4, x3 is 4, and j3 is 1. In embodiments, j.3 is 2. In embodiments, y”, x3 is 4, and j3 is 2, In embodiments when the cargo isO / \ ONf AW'- I#2[ V H \N <.-^ \\ / h-f NJ’y" H#1 * A, NH£ N v2zH £a PMO,° is directly attached to the free secondary amine of the morpholino ring of the 3' terminal nucleotide of a PMO.

[0191] In embodiments when ml is 0 or 1 and the compound comprises a C-terminal amino acid residue that has a side chain with a reactive moiety (e.g., lysine, glutamic acid, and the like), the compound may be coupled to the ASO through the C-terminal carboxylic acid (COOII) of the amino acid or through the side chain of the C-terminal amino acid. For example, when the compound comprises glutamic acid as a C-terminal amino acid, the ASO may be conjugated to the larger compound through the side chain of glutamic acid or through the C-terminal carboxylic acid of glutamic acid. In embodiments when the ASO is attached to the larger compound through the side chain a C-terminal amino acid residue, the C-terminal carboxylic acid may be modified or protected with a group other than a carboxylic acid. In embodiments when the ASO is attached to the larger compound through the C-terminal carboxylic acid of an amino acid residue having a side chain that comprises a reactive moiety, the reactive moiety of the side chain may be modified or protected.

[0192] Examples of compounds of Formula I include those listed in Table 2A, Table 2B, and Table 3C where Ac is -C(O)CHs; the cCPP is written as JA(cyclo[XAXRXcXDXFXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue, “miniPEG2” indicates -(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates ~-(CH2-CH2-O)#-CH2-CO- or -(CH2-CH -O)#-CH -CH2-CO- where # indicates to the number of -CII2-CII2-O- units; M' can be absent (i.e,, ml is 0) or any M' described herein (i.e., when ml is 1); and cargo can be any ASO described herein. In embodiments, the cargo is a PMO. In embodiments, the cargo is a PNA. In embodiments of the compounds of Table 2A, Table 2B, and Table 2C, each instance of “PEG2” refers to ~(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEGz”) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 2 A, Table 2B, and Table2C, each instance of “PEG?” refers to -(CH2-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 2A.SEQNo. Compound ID NO:Ac-KK-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-KRK-(2-Nal)-M'-cargoXI (Ac-KK-miniPEG2-K(cydo[FGFGRGRQ])-PEGi2-KRK-(2-Nal)-M'- 40, 30 cargo)Ac-K-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-KKRK-(2-Nal)-M'-cargoX2 (Ac-K-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-KKRK-(2-Nal)-M'- 40, 34 cargo)X3 Ac-KKK-K(cyclo[FGFGRGRQ])-PEGi2-RK-(2-Nal)-M'-cargo 89, 40 X4 Ac-KKK-K(cyclo[FGFGRGRQ])-PEGi2-rk-(2-nal)-M'-cargo 89, 40 X5 Ac-K(cyclo[FGFGRGRQ])-PEGi2-kkkr-(2-nal)-M'-cargo 40, 31 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip-BRBRB-M'- 18, 40, X6cargo 35 Ac-PK. KKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Na1-BRBRB-M'- cargo 18, 40, X7(Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-Nal-BRBRB- 36 M'-cargo)Ac-PKKKRKV-PEG2-K(cycl o[FGFGRGRQ] )-PECh-R-Bta-B-M'-cargo X8 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bta-B-M'- 18, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-BRB-Bip-M'-cargo13, 40, X9 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-BRB-Bip-M'- 29 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-BR-Bip-RB-M'- cargo 18, 40, X10(Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-BR-Bip-RB- 85 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-B-M'-cargoXI 1 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-B-M'-cargo) Ac-KKK-PEG2-K(cyc1o[FGFGRGRQ])-PEGi2-RK-(2-Nal)-M'-cargoX12 (Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-RK-(2-Nal)-M'- 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M'-cargoX13 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bip-M'-cargo) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'-cargoX14 13, 40 (Ac-KKKRK-nuniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'-cargo)Ac-PKKKRKV'-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8-RF-M’-cargo X15 (Ac-PKKKRKV-miniPEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8-RF-M'- 18, 38cargo)SEQ No. Compound ID NO: Ac-KKKRK-PEG2-K(cyclo[GfFGrGrQ])-PEGs-RF-M'-cargoX16 13, 44 (Ac-KKKRK-miniPEG2-K(cyclo[GffGrGrQ])-PEGs-RF-M'-cargo)Ac-kkkRK-PEG2-K(cyclo[GfFGrGrQ])-PEGs-RF-M'-cargoX17 11, 44 (Ac-kkkRK-miniPEG2-K(cyc1o[GfFGrGrQ])-PEG8-RF-M'-cargo)Ac-RBRRBR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-K-Bip-M'-cargoX19 20, 40 (Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-K-Bip-M'-cargo) Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'-cargoX20 12, 40 (Ac-kkkrk-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Nal-M'-cargoX21 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-M'-cargo) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-rf-M'-cargoX22 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-rf-M'-cargo)X23 Ac-RBKKBR-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M'-cargo 88, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FK-M'-cargoX24 13, 40 (Ac-KKKRK-nuniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FK-M'-cargo) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG«-R-Bta-M'-cargoX25 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-M'-cargo) X26 Ac-K(cyclo[FGFGRGRQ])-PEGi2-KKKRK-(2-Nal)-M' -cargo 40, 37 Ac-K(me)-K(me)-K(me)-R(me)-K(me)-PEG2-K(cyclo[FGFGRGRQ])- PEGs-RF-M '-cargoX27 14, 40 (Ac-K(me)-K(me)-K(me)-R(me)-K(me)-miniPEG2- K(cyclo[FGFGRGRQ])-PEGs-RF-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Val-Cit-M'-cargo X28 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Val-Cit- 18, 40 M'-cargo)Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-M'-caigoX29 (Ac-YAr\^RRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'- 21, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-M'-cargo X30 (Ac-PKKKRKV-minjPEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-M'- 18, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip-M'-cargoX31 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip-M'-cargo) Ac-PK. KKRKV-PEG2-K(cyclo[FGFRRRRQ])-PEGi2-(2-Nal)-M'-cargo X32 (Ac-PKKKRKV-miniPEG^-K(cyclo[FGFRRRRQ])-PEG12-(2-Nal)-M'- 18, 81 cargo)Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEGi2-dNal-M'-cargoX33 10, 45 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])-PEGi2-dNal-M'-cargo)Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEGi2-Nal-M'-cargoX34 10, 45 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])-PEG12-Nal-M,-cargo)Ac-pkkkrkv-PEG2-k(cyclo[fffrrrrQ])-PEGi2-dNal-M'-cargoX35 10, 82(Ac-pkkkrkv-miniPEG2-k(cyclo[fffrrrrQ])-PEGi2-dNal-M'-cargo)SEQ No. Compound ID NO: Ac-pkkkrkv-PEG2-k(cyclo[FGFRRRRQ])-PEGi2-dNal-M'-cargoX36 10, 81 (Ac-pkkkrkv-miniPEG2-k(cyclo[FGFRRRRQ])-PEGi2-dNal-M'-cargo) Ac-pkkkrkv-PEG2-k(cyclo[fGfGrGrQ])-PEGi2-dNal-M'-cargoX37 10, 83 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfGrGrQ])-PEGi2-dNal-M' -cargo)X38 Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8-Bip-M'-cargo 87, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PEG2-M'-cargo X39 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-miniPEG2- 13, 40 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bta-PEG2-M'-cargo X40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Bta- 13, 40 mi ni PE G? -M' -cargo)Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-M’-cargoX41 87, 40 (Ac-RBRRBR-K(cyclo[FGFGRGRQT)-miniPEG2-KF-PEG4-M'-cargo) Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFR-PEG4-M’-cargo X42 (Ac-PKKKRKV-mimPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFR- 18, 40 PEG4-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoX43 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-M'- 13, 40 cargo)Ac-PK. KKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-M,-cargo X44 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 18, 39 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoX45 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargoX46 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'- 13, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-M'-cargo X47 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-M'- 18, 39 cargo)Ac-KKKRK-PEG2-K([cyclo[FGFRHRHQ])-PEG2-RF-PEG4-M'-cargo X48 (Ac-KKKRK-miniPEG2-K([cyclo[FGFRHRHQ])-miniPEG2-RF-PEG4- 13, 42 M'-cargo)Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoX49 (Ac-KKFRK-miniPE&.-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-M'- 2, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])-PEG2-RF-PEG4-M'-cargoX50 (Ac-KKKRK-miniPEG2-K(cyclo[FGRGFGRQ]-miniPEG2-RF-PEG4-Ml- 13, 84 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFLRLRQ]-PEG2-RF-PEG4-M'-cargoX51 (Ac-KKKRK-miniPEG2-K(cyclo[FGFLRLRQ]-miniPEG2-RF-PEG4-M'- 13, 41cargo)SEQ No. Compound ID NO:Ac-KKKRK-PEG2-K(cyclo[FGFVRVRQ])-PEG2-RF-PEG4-M'-cargoX52 (Ac-KKKRK-miniPEG2-K(cyclo[FGFVRVRQ]-miniPEG2-RF-PEG4-M'- 13, 43 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoX53 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-M'- 13, cargo)Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoX54 (Ac-KKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-M'- 1, 40 cargo)Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargoX55 1, 40 (Ac-KKRK-mmiPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargo) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-PEG2-M'-cargo X56 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-miniPEG2- 13, 40 M'-cargo)Ac-YArVRRrGPR-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-M'- cargoX57 21, 39 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF- PEG4-M ’-cargo)Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEG8-M'-cargoX58 40, 18 (Ac-K(cyclo[FGFGRGRQ])-miniPEG2-PKKKRKV-PEG8-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-rf-PEG4-Bip-M’-cargo X59 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-rf-PEG4-Bip- 13, 40 M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG2-Bip-M’- cargoX60 18, 39 (Ac-PKKKRKV-mini PEG2-K(cycl o[FfFGRGRQ])-mmi PEG2-RF- miniPEG2-Bip-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo X61 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miiiiPEG2-RF-PEG4- 13, 40 Bip-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo X62 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-F- 13, 40 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ]-PEG2-RF-PEG4-R-M'-cargo X63 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-R- 13, 40 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ])-PEG2-RF-PEG4-F-M'-cargo X64 (Ac-KKKRK-miniPEG2-K(cyclo[FGFRRRRQ]-miniPEG2-RF-PEG4-F- 13, 81 M'-cargo)Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo X65 (Ac-KKFRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F- 2, 40M'-cargo)SEQ No. Compound ID NO:Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'- cargoX66 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- F-M'-cargo)Ac-RBRRBR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bta-M'- cargoX67 20, 40 (Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- Bta-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Nal-M'-cargo X68 (Ac-KKKRK-nuniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40 Nal-M'-cargo)Ac-KKKRK-PEG2-K([cycIo[FGFGRGRQ])-PECre-RF-PEG4-Nal-M'- cargoX69 13, 40 (Ac-KKKRK-miniPEG2-K([cyclo[FGFGRGRQ])-PEG8-RF-PEG4-Nal-M'- cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG2-Nal-M'- cargoX70 18, 39 (Ac-PKKKRKV-mini PEG2-K(cycl o[FfFGRGRQ])-mmi PEG2-RF- miniPEG2-Nal-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-Bip-M'-cargo X71 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4- 13, 40 Bip-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'- cargoX72 18, 40 (Ac-PKKKRKV-mini PEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- F-M' -cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-Bip-M'- cargoX73 18, 39 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- Bip-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-PEG2-(2- Nal)-M'-cargoX74 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-[2-Nal]- miniPEG2-(2~Nal)-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FfFGRGRQ])-PEGi2-(2-Nal)-PEG2-(2-Nal)- M'-cargoX75 13, 39 (Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEGi2-(2-Nal)-miniPEG2- (2-Nal)-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FfFGRGRQ])-PEGi2-Bip-PEG2-Bip-M'-cargo X76 (Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEGi2-Bip-miniPEG2- 13, 39Bip-M'-cargo)SEQ No. Compound ID NO:Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEGi2-Nal-PEG2-Nal-M'-cargoX77 (Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEGi2-Na1-miniPEG2-Nal-M'- 87,39 cargo)Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4-Nal-PEG2-Nal-M'-cargoX78 (Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4-Nal-miniPEG2-Nal-M'- 87, 40 cargo)X79 Ac-K(cyclo[FGFGRGRQ])-KKKRK-PEGi2-(2-Nal)-M'-cargo 40, 13 X80 Ac-KKK-K(cyclo[FGFGRGRQ])-RK-PEGi2-(2-Nal)-M'-cargo 89, 40 Ac-KKK-PEG2-K(cyclo[FGFGRGRQ])-RK-PEGi2-(2-Nal)-M'-cargoX81 (Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-RK-PEGi2-(2-Nal)-M'- 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-RF-PEG4-M'-cargoX82 18, 39 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQl)-RF-PEG4-M'-cargo) X83 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M!-cargo 1, 40 X84 Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bip-M'-cargo 12, 40 X85 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-M'-cargo 13, 40 X86 Ac-KKKRK-PEG4-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 13, 39 X87 Ac-KKKRK-PEG8-K(cyclo[FfFGRGRQ])-PEG«-RF-M'-cargo 13, 39 X88 Ac-KKRK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo I, 39 X89 Ac-KRK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 39 X90 Ac-RK-PEG2-K(cyclo[FfFGRGRQ])-PEGx-RF-M'-cargo 39 X91 Ac-RF-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 39 X92 Ac-KKKRK-PEG2-K(cyclo[FGFLRLRQ]-PEG2-RF-PEG4-M'-cargo 13, 41 X93 Ac-TKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 9, 40 X94 Ac-KKTRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 8, 40 Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'- X95 21, 40 cargoAc-KKKRK-PEG2-K(cyclo[G-f(N-me)-FGrGrQ])-PEG2-RG-PEG4-M'- X96 13, 55 cargoAc-KKKRK-PEG2-K(cyclo[G-f(N-me)-FGrGrQ])-PEG2-RF-PEG4-M'- X96.1 13, 55 cargoX97 Ac-KKKRK-PEG2-K(cyclo[Gf-Nal-GrGiQ])-PEG2-RF-PEG4-M'-cargo 13, 56 X98 Ac-KKKRK-PEG2-K(cyclo[GyYGrGrQ])-PEG2-RF-PEG4-M'-cargo 13, 58 X99 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-PEG4-M'-cargo 13, 40 XI 00 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG2-M'-cargo 13, 40 X101 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-M'-cargo 13, 40 XI 02 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-PEG4-M'-cargo 13, 40 X103 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFR-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-R-PEG4-M'- X104 13, 40cargoSEQ No. Compound ID NO:Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bip-R-PEG4-M'- X105 13, 40 cargoX106 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PEGi-M'-cargo 13, 40 XI 07 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG8-M'-cargo 13, 40 X108 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PECn-R-(3-Pyr)-PEG4-M'- XI 09 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(2-Pyr)-PEG4-M'- X110 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(4-Pyr)-PEG4-M'- Xlll 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Phe(3-CN)-PEG4-M'- XI 12 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PECh-R-Trp(5-F)-PEG4-M'- XI 13 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Tyr(Ph)-PEG4-M'- XI 14 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-(HoArg)-Bip-PEG4-M'- X115 13, 40 cargoXI 16 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-rf-PEGi-M,-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R(me)-F(me)-PEG4- XI 17 13, 40 M'-cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-(4-Pyr)-PEG4-Nal- XI 18 13, 40 M'-cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PEG4-F-M'- XI 19 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[4-Pyr-G-(4-Pyr)-GRGRQ])-PEG2-RF-PEGi- 13, 46 X120M'-cargoAc-KKKRK-PEG2-K(cyclo[4-Pyr-G-(4-Pyr)-GRGRQ])-PEG2-R-Bip- X121 13, 46 PEG4-M'-cargoX122 Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 13, 40 X123 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bta-PEG4-M'-cargo 13, 4013, 40, X124 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFRF-PEG4-M,-cargo33 13, 40, X125 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RRFF-PEG4-M'-cargo86 X126 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-M'-cargo 13, 4013, 40, X127 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KFKF-PEG4-M'-cargo32 X128 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-EF-PEG4-M'-cargo 13, 40 X129 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-PEG4-M'-cargo 13, 40X130 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bip-PEG4-M'-cargo 13, 40SEQ No. Compound ID NO: X131 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 1, 40 X132 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FGR-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[Phe(4-CN)-G-Phe(4-CN)-GRGRQ])-PEG2- XI 33 13, 59 RF-PEG4-M'-cargoX134 Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 13, 40 X135 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-K-PEG4-M'-cargo 1, 40 XI 36 Ac-KKRK-PEG2-K(cyclo[FGFGRrRQ])-PEG2-RF-PEG4-M'-cargo 1, 53 X137 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ]-PEG2-RF(I)-PEG4-M'-cargo 13, 40 X138 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FR-PEG4-M'-cargo 13, 40 X139 Ac-KKKRKR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-F-PEG4-M'-cargo 17, 40 X140 Ac-KKKRKF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG4-M,-cargo 16, 40 X141 Ac-KKKRK-PEG2-K(cyclo[GFRGFRGQ])-PEG2-RF-PEG4-M'-cargo 13, 57 X142 Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])-PEG2-RF-PEG4-M'-cargo 13, 84 XI 43 Ac-KKKRK-PEG2-K(cycl ofFFGRRGQ] )-PEG2-RF-PEG4-M'-cargo 13, 49 X144 Ac-KRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Ml-cargo 40 X145 Ac-RK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 40 XI 46 Ac-RF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 40 XI 47 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 1, 40 X148 Ac-KGKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 3, 40 X149 Ac-KKGRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Nf -cargo 4, 40 X150 Ac-KKKGK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 5, 40 X151 Ac-KKRKG-PEG2-K(cyclorFGFGRGRQl)-PEG2-RF-PEG4-M'-cargo 6, 40 X152 Ac-KKRKK-PEG2-K(cyclo[FGFG-Cit-GRQ])-PEG2-RF-PEG4-M'-cargo 7, 51 X153 Ac-KKRKK-PEG2-K(cyclo[FGFGRG-Cit-Q])-PEG2-RF-PEG4-M'-cargo 7, 52 XI 54 Ac-KKRKK-PEG2-K(cyclo[AGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 7, 47 X155 Ac-KKRKK-PEG2-K(cyclo[FGAGRGRQ])-PEG2-RF-PEG4-M'-cargo 7, 50 X156 Ac-KKKGK-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-M'-cargo 5, 39 XI 57 Ac-RF-PEG2-K(cyclo[FFFGRGRQ])-PEG2-RF-PEG4-M'-cargo 48 X158 Ac-KKFRK-PEG2-K(cyclo[FFFGRGRQ])-PEG2-RF-PEG4-M'-cargo 2, 48 X159 Ac-KKKRK-PEG2-K(cyclo[FRFRFRFQ])-PEG2-RF-PEG4-M'-cargo 13, 54 XI 60 Ac-KKKRK-PEG2-K(cyclo[FFFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 13, 48 X161 Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQl)-PEG2-RF-PEG4-F-M'-cargo 13, 81 XI 62 Ac-RF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 40 XI 63 Ac-KRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 40 XI 64 Ac-KFK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 40 XI 65 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-SF-PEG4-M'-cargo 13, 40 X166 Ac-KKKRK-PEG2-K(cyclo! FGFGRGRQ])-PEG2-RL-PEG4-M'-cargo 13, 40 X167 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RY-PEG4-M'-cargo 13, 40 XI 68 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RW-PEG4-M'-cargo 13, 40X169 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Cit-F-PEG4-M'-cargo 13, 40SEQ No. Compound ID NO: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-Bip-M'- X170 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-Bip-M'- X170.1 13, 40 cargoX171 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-R-Bip-PEGs-M'-cargo 13, 40 X172 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQl)-RF-PEG4-M'-cargo 18, 40 XI 73 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG4-M'-cargo 13, 40 X174 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG2-M'-cargo 13, 40 Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEGx-RF-PEG4-M'-cargo XI 75 40, 18 (See Formula II)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG2-F-PEG4-M'- X176 13, 40 cargo (See Formula II)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PEG4- X177 13, 40 M'-cargo (See Formula II)XI 78 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RPF-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGF-G(N-me)-RGRQ])-PEG2-RPF-PEG4-M'- XI 79 13, 60 cargoAc-KKKRK-PEG2-K(cyclo[F-G(N-me)-FGRGRQ])-PEG2-RPF-PEG4-M'- X180 13, 61 cargoX181 Ac-KKKRK-PEG2-K(cyclo[F / XFARGRQ])-PEG2-RF-PEG4-M'-cargo 13, 62 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Agp-Bip-PEG4-M'- X182 13, 40 cargoXI 83 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Agp-F-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFG-Agp-G-Agp-Q])-PEG2-RF-PEG4-M'- XI 84 13, 63cargoTable 2B.SEQ IDNo. CompoundNOS: X185 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-M'-cargo 13, 40 X186 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG2-M'-cargo 13, 40 XI 87 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Phg-PEG4-M'-cargo 13, 40 X188 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFE-M'-cargo 13, 40 XI 89 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-FIph-PEG4-M'-cargo 13, 40 XI 90 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Pcpa-F-PEG4-M'-cargo 13, 40 X191 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-rf-PEG4-M'-cargo 13, 40 X192 Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 12, 40 X193 Ac-KKKRK-PEG2-K(cyclo[Pcpa-G-Pcpa-GRGRQ])-PEG2-RF-PEG4-M'-cargo 13, 64X194 Ac-RFGRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-M'-cargo 22, 40Table 2C.SEQIDNo. CompoundNOS:Ac-KKKHH-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-F-PEG4-Bip-M'-cargo 15, 40 X195 (Ac-KKKHH-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-F-PEG4-Bip- M ’-cargo)Ac-K(me)-K(me)-K(me)-R(me)-K(me)-PEG2-K(cyclo[FGFGRGRQ])-PEG2- 14, 40 RF-PEGi-Bip-M'-cargoX196(Ac-K(me)-K(me)-K(me)-R(me)-K(me)-miniPEG2-K(cyclo[FGFGRGRQ])- miniPEG2-RF-PEG4-Bip-M'-cargo)Ac-KBKBKBRBK-PEG2-K(cyclo[FGFGRGRQ])- PEG2-RF-PEG4-Bip-M’- 23, 40 cargoX197(Ac-KBKBKBRBK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- Bip-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[GFRGFRGQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 57 XI 98 (Ac-KKKRK-miniPEG2-K(cyclo[GFRGFRGQ])-mmiPEG2-RF-PEG4-Bip-M'- cargo)Ac-KKKRK-PEG2-K(cyclo[GRFGRFGQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 66 X199 (Ac-KKKRK-miniPEG2-K(cyclo[GRFGRFGQ])-miniPEG2-RF-PEG4-Bip-M’- cargo)Ac-RFKKRFK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo 24, 40 X200 (Ac-RFKKRFK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip- M' -cargo)Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 24, 40 X201 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- M'-cargo)Ac-YArVRRiGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'- 21, 40 cargoX202(Ac-YArVRRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[RFGGRFGQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 67 X203 (Ac-KKKRK-miniPEG2-K(cyclo[RFGGRFGQ])-miniPEG2-RF-PEG4-Bip-M'- cargo)Ac-(N(k))-(N(k))-(N(k))-(N(Arg))-(N(k))-PEG2-K(cyclo[FGFGRGRQ])- 25, 40 PEG2-RF-PEG4-Bip-M'-cargoX204(Ac-(N(k))-(N(k))-(N(k))-(N(Arg))-(N(k))-miniPEG2-K(cyclo[FGFGRGRQ])- miniPEG2-RF-PEG4-Bip-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 40 X205 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-M'- cargo)Ac-(N(Arg))-B-(N(Arg))-(N(Arg))-B-(N(Arg))-K(cyclo[FGFGRGRQ])-PEG2- 26, 40 RF-PEG4-Bip-M'-cargoX206(Ac-(N(Arg))-B-(N(Arg))-(N( Arg))-B-(N(Arg))-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-M’-cargo)SEQ ID No. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FRF-PEG4-Bip-M'-cargo 13, 40 X207 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FRF-PEG4-Bip- M' -cargo)Ac-KKKRK-PEG2-K(cyclo[GFFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 65 X208 (Ac-KKKRK-miniPEG2-K(cyclo[GFFGRGRQ])-miniPEG2-RF-PEG4-Bip-M'-cargo)

[0193] It is understood that when SEQ ID NO(S) are listed after a compound, the SEQ ID NO(S) appear in the order (from left to right) in which they appear in the compound (from left to right). For example, Ac -KKKRK-PEG2-K(cyclo[GFFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo includes SEQ ID NOS. 13 and 65 and can be thought of as, for example, Ac-KKKRK(SEQ ID NO:13)-PEG2-K(cyclo[GFFGRGRQ(SEQ ID NO:65)])-PEG2-RF-PEG4-Bip-M'-cargo or Ac-(SEQ ID NO:13)-PEG2-K(cyclo[SEQ ID NO:65])-PEG2-RF-PEG4-Bip-M'-cargo.

[0194] In embodiments, a compound is selected from XI 5, X16, X17, X43 (FIG. 4JJ), X49 (FIG. 4LL), X50 (FIG. 4KK), X52, X54 (FIG. 411), X55 (FIG. 4HH), X62 (FIG. 4MM), X64, or X65, wherein “PEG2” is ~(CH2-CH2-O)2-CI I2-CH2-CO and cargo is [CAG]? (a PMO of the sequence 5'-CAGCAGCAGCAGCAGCAGCAG-3' (SEQ ID NO:76).

[0195] In embodiments, a compound comprising a delivery construct can be Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEGs-M'-cargo (SEQ ID NOS: 18, 38) where M' is present (m* is 1) or absent (m* is 0), PEG2is -(CH2-CH2-O)2-CH2-CH2-CO- or -(CH2-CH2-O)2-CH2-CO-, and PEGs is -(CH2-CH2-O)s-CH2-C(O)- or -(CH2-CH2-O)s-CH2-CH2-CO-.

[0196] Examples of compounds of Formula II include those listed in Table 2D where Ac is - C(O)CHs; the cCPP is written as JA(cyclo[XAXBXCXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGY indicates ~(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates -(CH2-CH2-O)#-CH2-CO- or -(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units, M' can be absent (i e., ml is 0) or any M' described herein (i.e., when ml is 1); and cargo can be any ASO described herein In embodiments, the cargo is a PMO. In embodiments, the cargo is a PNA. In embodiments of the compounds of Table 2D, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEGz”) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2, In embodiments of the compounds of Table2D, each instance of “PEG2” refers to -(CH?-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 2D.SEQ IDNo. CompoundNOS: Y1 Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEG8-RF-PEG4-M'-cargo 40, 18 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG2-F-PEG4-M'- Y2 13, 40 cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PEG4- Y3 13, 10M'-cargo

[0197] In embodiments, a compound is selected from Table 2A, 2B, 2C, or 2D. In embodiments, a compound is selected from Table 2A. In embodiments, a compound is selected from Table 2B. In embodiments, a compound is selected from Table 2C. In embodiments, a compound is selected from Table 2D.

[0198] In embodiments, a compound is selected from Table 2A, 2B, 2C, or 2D In embodiments, a compound is selected from Table 2A, 2B, 2C, or 2D where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 2A, 2B, 2C, or 2D where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 2A, where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 2A, where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 2B, where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 2B, where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 2C, where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 2C, where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 2D, where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 2D, where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3\

[0199] Further examples of compounds of Formula I include those listed in Table 3A, Table 3B, and Table 3C where Ac is -C(O)CH3; the cCPP is written as JA(cyclo[XAXBXCXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4,R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGz” indicates -(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates -(CH2-CH2-O)#-CH2-CO- or -(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' is absent (i.e., ml is 0) or Ml where Ml is04 ©vXA NH2H Ifwhere #2 is the point of attachment to the cargo, y″ is 4, x3 is 4, and j3 is 2; and cargo is a PMO conjugated to the delivery construct at the 3' terminus. In embodiments of the compounds of Table 3A, Table 3B, and Table 3C, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEGz”) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH -CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 3A, Table 3B, and Table 3C, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.

[0200] Table 3A.SEQ IDNo. CompoundNOS: Ac-KK-PEG2-K(cyclo[FGFGRGRQ])-PEG12-KRK-(2-Nal)-PMOJI 40, 30 (Ac-KK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-KRK-(2-Nal)-PMO) Ac-K-PEG2-K(cyclo[FGFGRGRQ])-PEG12-KKRK-(2-Nal)-PMOJ2 40, 34 (Ac-K-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-KKRK-(2-Nal)-PMO) J3 Ac-KKK-K(cyclo[FGFGRGRQ])-PEG12-RK-(2-Nal)-PMO 89, 40 J4 Ac-KKK-K(cyclo[FGFGRGRQ])-PEG12-rk-(2-nal)-PMO 89, 40 J5 Ac-K(cyclo[FGFGRGRQ])-PEG12-kkkr-(2-nal)-PMO 40, 3118, 40, J6 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-Bip-BRBRB-PMO35 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-Nal-BRBRB-PMO18, 40, J7 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-Nal-BRBRB- 36PMO)SEQ ID No. CompoundNOS: Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-B-PMOJ8 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bta-B- 18, 40 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG12-BRB-Bip-PMO 13, 40, J9(Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-BRB-Bip-PMO) 29 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-BR-Bip-RB-PMO18, 40, J10 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-BR-Bip-RB- 85 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-B-PMOJ11 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-B-PMO)Ac-KKK-PEG2-K(cyclo[FGFGRGRQ])-PEG12-RK-(2-Nal)-PMOJ12 40 (Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-RK-(2-Nal)-PMO) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PMOJ13 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-PMOJ14 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PMO)Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEGs-RF-PMOJ15 (Ac-PKKKRKV-miniPEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8-RF- 18, 38 PMO)Ac-KKKRK-PEG2-K(cyclo[GfFGiGrQ])-PEG8-RF-PMOJ16 13, 44 (Ac-KKKRK-miniPEG2-K(cyclo[GfFGrGrQ])-PEG8-RF-PMO)Ac-kkkRK-PEG2-K(cyclo[GtFGrGrQ])-PEG8-RF-PMOJ17 11, 44 (Ac-kkkRK-miniPEG2-K(cyclo[GfFGrGrQ])-PEG8-RF-PMO)Ac-RBRRBR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-K-Bip-PMOJ19 20, 40 (Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-K-Bip-PMO) Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PMOJ20 12, 40 (Ac-kkkrk-tniniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PMOJ21 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-rf-PMOJ22 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-rf-PMO)J23 Ac-RBKKBR-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PMO 88, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FK-PMOJ24 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FK-PMO) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-PMOJ25 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-PMO)J26 Ac-K(cyclo[FGFGRGRQ])-PEG12-KKKRK-(2-Nal)-PMO 40, 37 Ac-K(me)-K(me)-K(me)-R(me)-K(me)-PEG2-K(cyclo[FGFGRGRQ])- PEGs-RF-PMOJ27 14, 40 (Ac-K(me)-K(me)-K(me)-R(me)-K(me)-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PMO)SEQ ID No. CompoundNOS: Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Val-Cit-PMOJ28 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Val-Cit- 18, 40 PMO)Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PMOJ29 21, 40 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PMO) Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-(2-Nal)-PMOJ30 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-(2-Nal)-PMO) Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-Bip-PMOJ31 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-Bip-PMO) Ac-PKKKRKV-PEG2-K(cyclo[FGFRRRRQ])-PEG12-(2-Nal)-PMOJ32 18, 81 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFRRRRQ])-PEG12-(2-Nal)-PMO) Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEG12-dNal-PMOJ33 10, 45 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])-PEG12-dNal-PMO)Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEG12-Nal-PMOJ34 10, 45 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])-PEG12-Nal-PMO)Ac-pkkkrkv-PEG2-k(cyclo[fffrrrrQ])-PEG12-dNal-PMOJ35 10, 82 (Ac-pkkkrkv-miniPEG2-k(cyclo[fffrrrrQ])-PEG12-dNal-PMO)Ac-pkkkrkv-PEG2-k(cyclo[FGFRRRRQ])-PEG12-dNal-PMOJ36 10, 81 (Ac-pkkkrkv-miniPEG2-k(cyclo[FGFRRRRQ])-PEG12-dNal-PMO)Ac-pkkkrkv-PEG2-k(cyclo[fGfGrGrQ])-PEG12-dNal-PMOJ37 10, 83 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfGrGrQ])-PEG12-dNal-PMO)J38 Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8-Bip-PMO 87, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PEG2-PMOJ39 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-miniPEG2- 13, 40 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bta-PEG2-PMOJ40 (Ac-KKKRK -m iniPEG2-K(cy clo[FGFGR GRQ] )-rni niPEG2-R-Bta- 13, 40 miniPEG2-PMO)Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-PMOJ41 87, 40 (Ac-RBRRBR-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-PMO)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFR-PEG4-PMOJ42 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFR- 18, 40 PEG4-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMOJ43 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40 PMO)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-PMOJ44 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 18, 39 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMOJ45 (Ac-KKKRK -miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40PMO)SEQ ID No. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-PMOJ46 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-PMO) Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-PMOJ47 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4- 18, 39 PMO)Ac-KKKRK-PEG2-K([cyclo[FGFRHRHQ])-PEG2-RF-PEG4-PMO.148 (Ac-KKKRK-miniPEG2-K([cyclo[FGFRHRHQ])-miniPEG2-RF-PEG4- 13, 42 PMO)Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMOJ49 (Ac-KKFRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 2, 40 PMO)Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])-PEG2-RF-PEG4-PMOJ50 (Ac-KKKRK-miniPEG2-K(cyclo[FGRGFGRQ])-miniPEG2-RF-PEG4- 13, 84 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFLRLRQ])-PEG2-RF-PEG4-PMOJ51 ( Ac-KKKRK-mini PEG2-K(cyc] o[FGFLRLRQ])-mi ni PEG2-RF-PEG4- 13, 41 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFVRVRQ])-PEG2-RF-PEG4-PMOJ52 (Ac-KKKRK-miniPEG2-K(cyclo[FGFVRVRQ])-miniPEG2-RF-PEG4- 13, 43 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMOJ53 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, PMO)Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMOJ54 (Ac-KKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 1, 40 PMO)Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-PMOJ55 1, 40 (Ac-KKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-PMO) Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-PEG2-PMOJ56 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-miniPEG2- 13, 40 PMO)Ac-YArVRRrGPR-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-PMO J57 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF- 21, 39 PEG4-PMO)Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEG8-PMOJ58 40, 18 (Ac-K(cyclo[FGFGRGRQ])-miniPEG2-PKKKRKV-PEG8-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-rf-PEG4-Bip-PMOJ59 (Ac-KKKRK-miniPEG’2-K(cyclo[FGFGRGRQ])-miniPEG2-rf-PEG4-Bip- 13, 40 PMO)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG2-Bip-PMO.160 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF- 18, 39miniPEG2-Bip-PMO)SEQ ID No. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PMOJ61 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40 Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-PMOJ62 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F- 13, 40 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-R-PMOJ63 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-R- 13, 40 PMO)Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ])-PEG2-RF-PEG4-F-PMOJ64 (Ac-KKKRK-miniPEG2-K(cyclo[FGFRRRRQ])-miniPEG2-RF-PEG4-F- 13, 81 PMO)Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-PMOJ65 (Ac-KKFRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F- 2, 40 PMO)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-PMO J66 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 18, 40 F-PMO)Ac-RBRRBR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bta-PMO J67 (Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 20, 40 Bta-PMO)Ac-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Nal-PMO J68 (Ac-KKKRK-miniPEG2-K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40 Nal-PMO)Ac-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEGs-RF-PEG4-Nal-PMO J69 (Ac-KKKRK-miniPEG2-K([cyclo[FGFGRGRQ])-PEG8-RF-PEG4-Nal- 13, 40 PMO)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG2-Nal-PMO J70 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF- 18, 39 miniPEG2-Nal-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-Bip-PMOJ71 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4- 13, 40 Bip-PMO)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-PMO J72 (Ac-PKKKRKV-miniPEGi-K(cyclo[FGFGRGRQ])-miniPEG?-RF-PEG4- 18, 40 F-PMO)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-Bip-PMO J 73 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 18, 39 Bip-PMO)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG12-(2-Nal)-PEG2-(2- Nal)-PMOJ74 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-(2-Nal)-miniPEG2-(2-Nal)-PMO)SEQ ID No. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[FfFGRGRQ])-PEG12-(2-Nal)-PEG2-[2- Nal)-PMOJ75 13, 39 (Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEG12-(2-Nar)- miniPEG2-(2-Nal)-PMO)Ac-KKKRK-PEG2-K(cyclo[FfFGRGRQ])-PEG12-BiP-PEG2-BiP-PMO J76 (Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEG12-BiP-miniPEG2- 13, 39 BiP-PMO)Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEG12-Nal-PEG2-Nal-PMOJ77 87, 39 (Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEG12-Nal-miniPEG2-Nal-PMO) Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4-Nal-PEG2-Nal-PMOJ 78 87, 40 (Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4-Nal-miniPEG2-Nal-PMO) J79 Ac-K(cyclo[FGFGRGRQ])-KKKRK-PEGi2-(2-Nal)-PMO 89, 13 J80 Ac-KKK-K(cyclo[FGFGRGRQ])-RK-PEG12-(2-Nal)-PMO 13, 40 Ac-KKK-PEG2-K(cyclo[FGFGRGRQ])-RK-PEG12-(2-Nal)-PMOJ81 40 (Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-RK-PEG12-(2-Nal)-PMO) Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-RF-PEG4-PMOJ82 18, 39 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-RF-PEG4-PMO)J 83 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PMO 1, 40 J 84 Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PMO 12, 40 J85 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PMO 13, 40 J86 Ac-KKKRK-PEG4-K(cyclo[FfFGRGRQ])-PEG8-RF-PMO 13, 39 J87 Ac-KKKRK-PEG8-K(cyclo[FfFGRGRQ])-PEG8-RF-PMO 13, 39 J88 Ac-KKRK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PMO 1, 39 J89 Ac-KRK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PMO 39 J90 Ac-RK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PMO 39 J91 Ac-RF-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PMO 39 J92 Ac-KKKRK-PEG2-K(cyclo[FGFLRLRQ])-PEG2-RF-PEG4-PMO 13, 41 J93 Ac-TKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 9, 40 J94 Ac-KKTRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 8, 40 J95 Ac-YArVRRiGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-PMO 21, 40 J96 Ac-KKKRK-PEG2-K(cyclo[G-f(N-me)-FGrGrQ])-PEG2-RG-PEG4-PMO 13, 55 J96.1 Ac-KKKRK-PEG2-K(cyclo[G-f'(N-me)-FGrGrQ])-PEG2-RF-PEG4-PMO 13, 55 J97 Ac-KKKRK-PEG2-K(cyclo[Gf-Nal-GrGrQ])-PEG2-RF-PEG4-PMO 13, 56 J98 Ac-KKKRK-PEG2-K(cyclo[GyYGrGrQ])-PEG2-RF-PEG4-PMO 13, 58 J99 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-PEG4-PMO 13, 40 J100 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG2-PMO 13, 40 J101 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-PMO 13, 40 J102 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-PEG4-PMO 13, 40 J103 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFR-PEG4-PMO 13, 40J104 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-R-PEG4-PMO 13, 40SEQ ID No. CompoundNOS:J 105 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bip-R-PEG4-PMO 13, 40 J 106 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PEG4-PMO 13, 40 J107 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG«-PMO 13, 40 J108 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-PMO 13, 40 J109 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(3-Pyr)-PEG4-PMO 13, 40 J110 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(2-Pyr)-PEG4-PMO 13, 40 Jill2Xc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(4-Pyr)-PEG4-PMO 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Phe(3-CN)-PEG4- J112 13, 40 PMOJ113 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Trp(5-F)-PEG4-PMO 13, 40 J114 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Tyr(Ph)-PEG4-PMO 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-HoArg-Bip-PEG4- JI 15 13, 40 PMOJ116 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-rf-PEG4-PMO 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R(me)-F(me)-PEG4- J117 13, 40 PMOAc-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEGs-R-(4-Pyr)-PEG4-Nal- J118 13, 40 PMOJ119 Ac-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEGs-R-NaI-PEG4-F-PMO 13, 40 Ac-KKKRK-PEG2-K(cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ])-PEG2-RF- 13, 46 JI 20PEG4-PMOAc-KKKRK-PEG2-K(cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ])-PEG2-R-Bip- J121 13, 46 PEG4-PMOJI 22 Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 13, 40 J123 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bta-PEG4-PMO 13, 4013, 40, J 124 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFRF-PEG4-PMO33 13, 40, J125 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RRFF-PEG4-PMO86 J 126 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-PMO 13, 4013, 40, JI 27 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KFKF-PEG4-PMO32 J128 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-EF-PEG4-PMO 13, 40 J 129 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-PEG4-PMO 13, 40 J 130 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bip-PEG4-PMO 13, 40 J131 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 1, 40 J 132 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FGR-PEG4-PMO 13, 40 Ac-KKKRK-PEG2-K(Phe(4-CN)-G-Phe(4-CN)-GRGRQ)-PEG2-RF- J133 13, 59 PEG4-PMOJ134 Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 13, 40J135 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-K-PEG4-PMO 1, 40SEQ ID No. CompoundNOS: J136 Ac-KKRK-PEG2-K(cyclo[FGFGRrRQ])-PEG2-RF-PEG4-PMO 1, 53 J 137 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ]-PEG2-R-F(I)-PEG4-PMO 13, 40 J138 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FR-PEG4-PMO 13, 40 J139 Ac-KKKRKR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-F-PEG4-PMO 17, 40 J140 Ac-KKKRKF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG4-PMO 16, 40 J141 Ac-KKKRK-PEG2-K(cyclo[GFRGFRGQ])-PEG2-RF-PEG4-PMO 13, 57 JI 42 / Xc-KKKRK-PEG2-K(cycio[FGRGFGRQ])-PEG2-RF-PEG4-PMO 13, 84 J143 Ac-KKKRK-PEG2-K(cyc]o[FFGRRGQ])-PEG2-RF-PEG4-PMO 13, 49 J144 Ac-KRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 40 J145 Ac-RK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 40 J146 Ac-RF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 40 J147 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 1, 40 J 148 Ac-KGKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 3, 40 J 149 Ac-KKGRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 4, 40 J 150 Ac-KKKGK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 5, 40 J 151 Ac-KKRKG-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 6, 40 J152 Ac-KKRKK-PEG2-K(cyclo[FGFG-Cit-GRQ])-PEG2-RF-PEG4-PMO 7, 51 J153 Ac-KKRKK-PEG2-K(cyclo[FGFGRG-Cit-Q])-PEG2-RF-PEG4-PMO 7, 52 J154 Ac-KKRKK-PEG2-K(cyclo[AGFGRGRQ])-PEG2-RF-PEG4-PMO 7, 47 J155 Ac-KKRKK-PEG2-K(cyclo[FGAGRGRQ])-PEG2-RF-PEG4-PMO 7, 50 J156 Ac-KKKGK-PEG2-K(cyclo[FfF'GRGRQ])-PEG2-RF-PEG4-PMO 5, 39 J157 Ac-RF-PEG2-K(cyclo[FFFGRGRQ]-PEG2-RF-PEG4-PMO 48 JI 58 Ac-KKFRK-PEG2-K(cyc1o[FFFGRGRQ]-PEG2-RF-PEG4-PMO 2, 48 J159 Ac-KKKRK-PEG2-K(cyclo[FRFRFRFQ]-PEG2-RF-PEG4-PMO 13, 54 J160 Ac-KKKRK-PEG2-K(cyclo[FFFGRGRQ]-PEG2-RF-PEG4-F-PMO 13, 48 J161 Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ]-PEG2-RF-PEG4-F-PMO 13, 81 J 162 Ac-RF-PEG2-K(cyclo[FGFGRGRQ]-PEG2-RF-PEG4-F-PMO 40 J 163 Ac-KRK-PEG2-K(cyclo[FGFGRGRQ]-PEG2-RF-PEG4-F-PMO 40 J 164 Ac-KFK-PEG2-K(cyclo[FGFGRGRQ]-PEG2-RF-PEG4-F-PMO 40 J 165 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-SF-PEG4-PMO 13, 40 J166 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQl)-PEG2-RL-PEG4-PMO 13, 40 J167 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQl)-PEG2-RY-PEG4-PMO 13, 40 J168 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RW-PEG4-PMO 13, 40 J169 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Cit-F-PEG4-PMO 13, 40 JI 70 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-Bip-PMO 13, 40 I 70.1 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-Bip-PMO 13, 40 J171 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-R-Bip-PEGx-PMO 13, 40 J172 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG4-PMO 18, 40J173 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG4-PMO 13, 40SEQ ID No. CompoundNOS: J 174 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG2-PMO 13, 40 Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEGs-RF-PEG4-PMOJ175 40, 18 (See Formula II)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG2-F-PEG4-PMO J 176 13, 40 (See Formula 11)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PEG4- J177 13, 40 PMO (See Formula II)J 178 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RPF-PEG4-PMO 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGF-G(N-me)-RGRQ])-PEG2-RPF-PEG4- J179 13, 60 PMOAc-KKKRK-PEG2-K(cyclo[F-G(N-nie)-FGRGRQ])-PEG2-RPF-PEG4- J 180 13, 61 PMOJ181 Ac-KKKRK-PEG2-K(cyclo[FAFARGRQ])-PEG2-RF-PEG4-PMO 13, 62 J182 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Agp-Bip-PEG4-PMO 13, 40 JI 83 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Agp-F-PEG4-PMO 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFG-Agp-G-Agp-Q])-PEG2-RF-PEG4- JI 84 13, 63PMOTable 3B.SEQ IDNo. CompoundNOS: J185 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-PMO 13, 40 J186 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG2~PMO 13, 40 J 187 Ac-KKKRK-PEG2-K(cyclorFGFGRGRQ])-PEG2-R-Phg-PEG4-PMO 13, 40 J 188 Ac-KKKRK-PEG2-K(cyclorFGFGRGRQl)-PEG2-RFE-PMO 13, 40 J 189 Ac-KKKRK-PEG2-K(cyclorFGFGRGRQ])-PEG2-R-Hph-PEG4-PMO 13, 40 J190 Ac-KKKRK-PEG2-K(cyclorFGFGRGRQ])-PEG2-Pcpa-F-PEG4-PMO 13, 40 J191 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-rf-PEG4-PMO 13, 40 J192 Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO 12, 40 Ac-KKKRK-PEG2-K(cyclo[Pcpa-G-Pcpa-GRGRQ])-PEG2-RF-PEG4- JI 93 13, 64 PMOJ 194 Ac-RFGRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-PMO 22, 40Table 3C.SEQ IDNo. CompoundNOS: Ac-KKKHH-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PMOJI 95 (Ac-KKKHH-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 15, 40Bip-PMO)SEQ ID No. CompoundNOS: Ac-K(me)-K(me)-K(me)-R(me)-K(me)-PEG2-K(cyclo[FGFGRGRQ])- PECn-RF-PEG4-Bip-PMOJI 96 14, 40 (Ac-K(me)-K(me)-K(me)-R(me)-K(me)-miniPEG2- K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-PMO)Ac-KBKBKBRBK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip- PMOJ 197 23, 40 (Ac-KBKBKBRBK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF- PEG4-Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[GFRGFRGQ])-PEG2-RF-PEG4-Bip-PMOJ 198 (Ac-KKKRK-mimPEG2-K(cyclo[GFRGFRGQ])-miniPEG2-RF-PEG4- 13, 57 Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[GRFGRFGQ])-PEG2-RF-PEG4-Bip-PMOJ199 (Ac-KKKRK-miniPEG2-K(cyclo[GRFGRFGQ])-miniPEG2-RF-PEG4- 13, 66 Bip-PMO)Ac-RFKKRFK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PMO J200 (Ac-RFKKRFK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 24, 40 Bip-PMO)Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO J201 (Ac-YArVRRrGPR-miniPEG^-K(cyclo[FGFGRGRQ])-miniPEG2-RF- 24, 40 PEG4-PMO)Ac-YArVRRi-GPR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip- PMOJ202 21, 40 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF- PEG4-Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[RFGGRFGQ])-PEG2-RF-PEG4-Bip-PMOJ203 (Ac-KKKRK-mimPEG2-K(cyclo[RFGGRFGQ])-miniPEG2-RF-PEG4- 13, 67 Bip-PMO)Ac-(N(k))-(N(k))-(N(k))-(N(Arg))-(N(k))-PEG2-K(cyclo[FGFGRGRQ])- PEG2-RF-PEG4-Bip-PMOJ204 25, 40 (Ac-(N(k))-(N(k))-(N(k))-(N(Arg))-(N(k))-miniPEG2- K(cYclo[FGFGRGRQl)-miniPEG2-RF-PEG4-Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PMOJ205 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40 Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PNAJ205.1 (Ac-KKKRK-miiiiPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 13, 40 Bip-PNA)Ac-(N(Arg))-B-(N(Arg))-(N(Arg))-B-(N(Arg))-K(cyclo[FGFGRGRQ])- miniPEG2-RF-PEG4-Bip-PMOJ206 26, 40 (Ac-(N(Arg))-B-(N(Arg))-(N(Arg))-B-QST(Arg))-K(cyclo[FGFGRGRQ])- mini PEG2-RF-PEG4-Bip-PMO)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])PEG2-FRF-PEG4-Bip-PMOJ207 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FRF-PEG4- 13, 40Bip-PMO)SEQ ID No. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[GFFGRGRQ])-PEG2-RF-PEG4-Bip-PMOJ208 (Ac-KKKRK-miniPEG2-K(cyclo[GFFGRGRQ])-miniPEG2-RF-PEG4- 13, 65Bip-PMO)

[0201] In embodiments, a compound is selected from JI 5, J16, J17, J43 (FIG. 4JJ), J49 (FIG.4LL), J50 (FIG. 4KK), J52, J54 (FIG. 411), J55 (FIG. 4HH), J62 (FIG. 4MM), J64, or J65, wherein “PEG2” is -(CH2-CH2 O)2-CH2-CH2-CO and PMO is [CAG]? (a PMO of the sequence 5'-CAGCAGCAGCAGCAGCAGCAG-3' (SEQ ID NO: 76).

[0202] In embodiments, a compound comprising a delivery construct can be Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEGs-PMO (SEQ ID NOS: 18, 38) where PEG? is -(CH2-CH2-O)2-CH2-CH2-CO- or (CH2-CH2-O)2-CH2-CO- andPEGs is (CH2-CH2-O)s-CH2-C(O)- or ~(CH2-CH2-O)S-CH2-CH2-CO-

[0203] Further examples of compounds of Formula II include those listed in Table 3D where Ac is -C(O)CH3; the cCPP is written as JA(cyclo[X 'XBXcXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R3, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGz” indicates -(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates -(CH2-CH2- O) -CH2-CO- or (CH2-CE[2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' is absent (i.e., ml is 0); and cargo is a PMO to the delivery construct at the 3' terminus. In embodiments of the compounds of Table 3D, each instance of “PEG?” refers to - (CH2-CH2-O)2-CH2-CO- (i.e., “miniPEGz”) and each instance of “PEG#” refers to (CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 3D, each instance of “PEG?” refers to ~-(CH2-CH2-O)2-CH?-CH?-CO- and each instance of “PEG*” refers to ~(CH2-CH2-O)#-CII2-CIl2-CO- where # is an integer greater than 2.Table 31).SEQ IDNo. CompoundNOS:Y4 AC-K(CVC1O[FGFGRGRQ])-PEG2-PKKKRKV-PEGB-RF-PEG4-PMO 40, 18 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG2-F-PEG4- Y5 13, 40 PMOAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PEG4- Y6 13, 40PMO

[0204] In embodiments, a compound is selected from Table 3A, 3B, 3C, or 3D. In embodiments, a compound is selected from Table 3A. In embodiments, a compound is selected from Table 3B. In embodiments, a compound is selected from Table 3C. In embodiments, a compound is selected from Table 3D. In embodiments, a compound is selected from Table 3A, where the PMO is of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 3B, where the PMO is of the sequence 5’-CAG-CAG-CAG-CAG-C AG-CAG-CAG-3’. In embodiments, a compound is selected from Table 3C, where the PMO is of the sequence 5 ’-C AG-C AG-C AG-C AG-C AG-C AG-C AG-3’. In embodiments, a compound is selected from Table 3D, where the PMO is of the sequence 5’-CAG-C AG-C AG-C AG-C AG-C AG-C AG-3 ’.

[0205] In embodiments, a compound is selected from a compound shown in FIG, 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, 41, 4J, 4K, 4L, 4M, 4N, 40, 4P, 4Q, 4R, 4S, 4T, 4U, 4V, 4W, 4X, 4Y, 4Z, 4AA, 4BB, 4CC, 4DD, 4EE, 4FF, 4GG, 4HH, 411, 4JJ, 4KK, 4LL, or 4MM where RPMOis shown in FIG. 5.

[0206] In embodiments, a compound is selected from a compound shown in FIG. 4A, 4B, 4C, 4D, 4E, 4F, or 4G where RPMOis shown in FIG, 5.

[0207] In embodiments, a compound is selected from a compound shown in FIG, 4H, 41, 4 J, 4K, 4L, 4M, 4N, or 40 'where RPMOis shown in FIG. 5,

[0208] In embodiments, a compound is selected from a compound shown in FIG. 4P, 4Q, 4R, 4S, 4T, or 4U where RPMOis shown in FIG. 5.

[0209] In embodiments, a compound is selected from a compound shown in FIG. 4H, 4J, 4L, 4V, 4LL, 4KK, 4JJ, 411, 4HH, 4FF, 4EE, 4DD, 4CC, 4BB, 4AA, 4Z, 4Y, 4X, 4W where RPMOis shown in FIG. 5.

[0210] In embodiments, a compound is selected from a compound shown in FIG, 4N, and 4GG, 4M M, where RPMt)is shown in FIG. 5.

[0211] In embodiments, a compound is the compound of FIG. 4A w’here RPMOis showm in FIG.5, In embodiments, a compound is the compound of FIG, 4B where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4C where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4D where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4E where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4F where RPMOis shown in FIG. 5. Inembodiments, a compound is the compound of FIG. 4G where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4H where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 41 where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4 J where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4K where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4L where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4M where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4N where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 40 where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4P where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4Q where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4R where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4S where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4T where RPMOis shown in FIG. 5.In embodiments, a compound is the compound of FIG. 4U where RPMOis shown in FIG. 5.

[0212] In embodiments, a compound is the compound of FIG. 4V where RPMOis shown in FIG.5. In embodiments, a compound is the compound of FIG. 4W where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4X where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4Y where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4Z where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4AA where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4BB where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4CC where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4DD where RPMOis shown in FIG. 5. EE where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4FF where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4GG where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4IIH where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 411 where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4JJ where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4KK where RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4LLwhere RPMOis shown in FIG. 5. In embodiments, a compound is the compound of FIG. 4MM where RPMOis shown in FIG. 5.

[0213] In embodiments, the compound of Formula I may be of Formula III:Formula III■ 1 A3H, R5in? H A,..,- IF. / ,..(AA3F, i V Gp'hXi Y 4AA2| asy (AMr^^V3^ xi O ii < U a4! Y& HQ >..-.4 R* c / 'SH^ -Zv.o O,.,„ ^V.. RSNH HRR* >■■•< %0 or a pharmaceutically acceptable salt thereof, where:wl, w2, and w3 are each independently 0 or 1;xl, x2, and x3 are each independently an integer from 1 to 14;j 1, j2, and j3 are each independently an integer from 1 to 4; andR20, AA1, al, y, 11, R1, R2, R3, R4, R5, R6, R7, AA2, a2, AA3, a3, AA4, a4, ml, M', and cargo are defined herein, where at least one of a2, a3, and a4 is 1 and at least one of w2 and w3 is 1.

[0214] In embodiments, ml is 0. In such embodiments, the delivery construct is directly bonded to the cargo.

[0215] wl, w2, and w3 are each independently 0 or 1. wl can be 0. wl can be 1. w2 can be 0. w2 can be 1. w3 can be 0. w3 can be 1. In embodiments, at least one of w2 and w3 is 1.

[0216] In embodiments, al is 1, a2 is 1, a3 is 0, a4 is 0, wl is 1, w2 is 1, and w3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, wl is 1, w2 is 1, and w3 is 0. In embodiments, al is 0, a2 is I, a3 is 0, wl is 0, w2 is 1, and w3 is 0.

[0217] In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 0, wl is 1, w2 is 1, and w3 is 1. In embodiments, al is 0, a2 is 0, wl is 1, w2 is 1, and w3 is 1. In embodiments, al is 0, a2 is 0, wl is 0, w2 is 1, and w3 is 1.

[0218] In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 1, wl is 1, w2 is 1, and w3 is 1. In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 1, wl is 1, w2 is 1, and w3 is 1. In embodiments, al is 1, a2 is 0, a3 is 1, a4 is 1, wl is 0, w2 is I, and w3 is 1

[0219] In embodiments, al is 1, a2 is 1, a3 is 1, a4 is 0, wl is l,w2 is 1, and w3 is 0. In embodiments, al is 1, a2 is 1, a3 is 1, a4 is 0, wl is 1, w2 is 1, and w3 is 0. In embodiments, al is 1, a2 is 1, a3 is 1, a4 is 0, wl is 0, w2 is 1, and w3 is 0.

[0220] In embodiments, al is 1, a2 is 1, a3 is 0, a4 is 0, wl is 1, w2 is 1, and w3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, a4 is 0, wl is 1, w2 is 1, and w3 is 0. In embodiments, al is 0, a2 is 1, a3 is 0, a4 is 0, wl is 0, w2 is 1, and w3 is 0.

[0221] xl, x2, and x3 are each independently an integer from 1 to 14. Each of xl, x2, and x3 present in the compound are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In embodiments, each of xl, x2, and x3 present in the compound are each independently 2, 4, 6, 8, 10, or 12. In embodiments, each of xl, x2, and x3 present in the compound are each independently 2, 4, 8, or 12.

[0222] When wl is 1, xl can be 2, 4, 8, or 12. When wl is 1, xl can be 2. When wl is 1, xl can be 4. When wl is 1, xl can be 8. When wl is 1, xl can be 12.

[0223] When w2 is 1, x2 can be 2, 4, 8, or 12. When w2 is 1, x2 can be 2. When w2 is 1, x2 can be 4. When w2 is 1, x2 can be 8. When w2 is 1, x2 can be 12.

[0224] When w3 is 1, x3 can be 2, 4, 8, or 12. When w3 is 1, x2 can be 2. When w3 is 1, x3 can be 4. When w3 is 1, x2 can be 8. When w3 is 1, x3 can be 12.

[0225] j 1, j2, and j3 are each independently an integer from 1 to 4. 0. j 1 can be 1. j 1 can be 2. j can be 3. j 1 can be 4. j2 can be 1. j2 can be 2, j2 can be 3. j2 can be 4. j3 can be 1. j3 can be 2, j3 can be 3. j3 can be 4.

[0226] In embodiments when wl is 1, xl can be 2, 4, 8, or 12, and jl can be 1 or 2. In embodiments when wl is 1, xl can be 2 and j 1 can be 1. In embodiments when wl is I, xl can be 2 and j 1 can be 2. In embodiments when wl is 1, xl can be 4 and j 1 can be 1. In embodiments when wl is 1, xl can be 4 and j 1 can be 2. In embodiments when wl is 1, xl can be 8 and j 1 canbe 1. In embodiments when wl is i, xl can be 8 and j 1 can be 2. In embodiments when wl is 1, xl can be 12 andjl can be 1. In embodiments when wl is 1, xl can be 12 andjl can be 2.

[0227] In embodiments when w2 is 1, x2 can be 2, 4, 8, or 12, and j2 can be 1 or 2. In embodiments when w2 is 1, x2 can be 2 and j2 can be 1. In embodiments when w2 is 1, x2 can be 2 and j2 can be 2. In embodiments when w2 is 1, x2 can be 4 and j2 can be 1. In embodiments when w2 is 1, x2 can be 4 and j2 can be 2. In embodiments when w2 is 1, x2 can be 8 and j2 can be 1. In embodiments when w2 is 1, x2 can be 8 and j2 can be 2. In embodiments when w2 is 1, x2 can be 12 and j2 can be 1. In embodiments when w2 is 1, x2 can be 12 and j2 can be 2.

[0228] In embodiments when w3 is 1, x3 can be 2, 4, 8, or 12, and j3 can be 1 or 2. In embodiments when w3 is 1, x3 can be 2 and j3 can be 1. In embodiments when w3 is 1, x3 can be 2 and j3 can be 2. In embodiments when w3 is 1, x3 can be 4 and j3 can be 1. In embodiments when w3 is 1, x3 can be 4 and j3 can be 2. In embodiments when w3 is 1, x3 can be 8 and j3 can be 1. In embodiments when w3 is 1, x3 can be 8 and j3 can be 2. In embodiments when w3 is 1, x3 can be 12 and j3 can be 1. In embodiments when w3 is 1, x3 can be 12 and j3 can be 2.

[0229] In embodiments, the compound of Formula III may be of Formula A:Formula A:Formula Aor a pharmaceutically acceptable salt thereofwhere a3 is 1 and R20, AA1, al, xl, j 1, wl, y, n, R1, R2, R3, R4, R\ Rb, R7, x2, j2, AA3, ml, NT, and cargo are defined herein.

[0230] Examples of compounds of Formula A include those listed in Table 4A and Table 4B where Ac is -C(O)CH3; the cCPP is written as JA(cyclo[XAXBXcXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEG2” indicates –(CH2-CH2-O)2-CH2-CO-; “PEG>y” indicates -(CH2-CH2-O)#-CH2-CO- or –(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' can be absent (i.e., ml is 0) or any M' described herein (i.e., when ml is 1); and cargo can be any ASO described herein. In embodiments, the cargo is a PMO. In embodiments, the cargo is a PNA. In embodiments of the compounds of Table 4A and Table 4B, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEGz”) and each instance of “PEG#” refers to –(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments ofthe compounds of Table 4A and Table 4B, each instance of “PEG?” refers to -(CH2-CH2-O)?-CH2-CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 4A.No. Compound SEQ ID NOS:Ac-KK-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-KRK-(2-Nal)-M'- cargoAl 40, 30 (Ac-KK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-KRK-(2-Nal)- M'-cargo)Ac-K-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-KKRK-(2-Nal)-M'- cargoA2 40, 34 (Ac-K-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-KKRK-(2-Nal)- M'-cargo)A3 Ac-K(cyclo[FGFGRGRQ])-PEGi2-KKKRK-(2-Nal)-M'-cargo 40, 37 A4 Ac-KKK-K(cyclo[FGFGRGRQ])-PEGi2-RK-(2-Nal)-M'-cargo 89, 40 A5 Ac-KKK-K(cyclo[FGFGRGRQ])-PEGi2-rk-(2-nal)-M'-cargo 89, 40 A6 Ac-K(cyclo[FGFGRGRQ])-PEGi2-kkkr-(2-nal)-M'-cargo 40, 31 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip- BRBRB-M'-cargoA7 18, 40, 35 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip- BRBRB-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-Nal- BRBRB-M'-cargoA8 18, 40, 36 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-Nal- BRBRB-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bta-B- M'-cargoA9 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta- B-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-BRB-Bip-M'- cargoA10 13, 40, 29 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-BRB- Bip-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-BR-Bip- RB-M'-cargoAll 18, 40, 85 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-BR- Bip-RB-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-B-M'-cargoA12 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PECre-RF-B-M'- 13, 40 cargo)Ac-KKK-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-RK-(2-Nal)-M'- A13 40cargoNo. Compound SEQ ID NOS: (Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-RK-(2-Nal)- M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M'-cargoA14 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-M'-cargoA15 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQJ)-PEG8-RF-M’- 13, 40 cargo)Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8-RF- M'-cargo 18, 38 A16(Ac-PKKKRKV-miniPEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8- RF-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[GfFGrGrQ])-PEGs-RF-M'-cargo13, 44 A17 (Ac-KKKRK-miniPEG2-K(cyclo[GfFGrGrQ])-PEGs-RF-M’- cargo)Ac-kkkRK-PEG2-K(cyclo[GfFGrGrQ])-PEG8-RF-M'-cargo 11, 44 A18(Ac-kkkRK-miniPEG2-K(cyclo[GfFGrGrQ])-PEG^-RF-M'-cargo)Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8-RF- M'-cargo 18, 38 A19(Ac-PKKKRKV-miniPEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8- RF-M' -cargo)Ac-RBRRBR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-K-Bip-M'- cargoA20 20, 40 (Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-K-Bip- M'-cargo)Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEGs-RF-M' -cargoA21 (Ac-kkkrk-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'- 12, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Nal-M'-cargoA22 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-rf-M'-cargoA23 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-rf-M'- 13, 40 cargo)A24 Ac-RBKKBR-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M'-cargo 88, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FK-M'-cargoA25 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FK- 13, 40 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-M'-cargoA26 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-M'- 13, 40 cargo)Ac-K(me)-K(me)-K(me)-R(me)-K(me)-PEG2- A27 14, 40 K(cyclo[FGFGRGRQ])-PEG8-RF-M'-cargoNo. Compound SEQ ID NOS: (Ac-K(me)-K(me)-K(me)-R(me)-K(me)-miniPEG2- K(cyclo[FGFGRGRQ])-PEGs-RF-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[rGFGRGRQ])-PEG2-Val-Cit-M'- cargoA28 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2- Val-Cit-M'-cargo)Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-M'- cargoA29 21, 40 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF- M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-M'- cargoA30 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2- Nal)-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG]2-Bip-M'- cargoA31 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-Bip- M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFRRRRQ])-PEGi2-(2-Nal)-M'- cargoA32 18, 81 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFRRRRQ])-PEGi2-(2-Nal)-M'-cargo)Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEGi2-dNal-M'-cargoA33 10, 45 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])-PEGi2-dNal-M'-cargo)Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEGi2-Nal-M'-cargoA34 10, 45 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])-PEGi2-Nal-M'-cargo)Ac-pkkkrkv-PEG2-k(cyclo[fffrrri" Q])-PEGi2-dNal-M'-cargoA35 10, 82 (Ac-pkkkrkv-miniPEG2-k(cyclo[fffrrrrQ])-PEGi2-dNal-M'-cargo)Ac-pkkkrkv-PEG2-k(cyclo[FGFRRRRQ])-PEGi2-dNal-M'-cargoA36 (Ac-pkkkrkv-miniPEG2-k(cyclo[FGFRRRRQ])-PEGi2-dNal-M’- 10, 81 cargo)Ac-pkkkrkv-PEG2-k(cyclo[fGfGrGrQ])-PEGi2-dNal-M'-cargoA37 (Ac-pkkkrkv-miniPEG2-k(cyclo[fGfGrGrQ])-PEGi2-dNal-M'- 10, 83 cargo)Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8-Bip-M'-cargoA38 87, 40 (Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8-Bip-M'-cargo)A39 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-M'-cargo 1, 40 A40 Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bip-M'-cargo 12, 40 A41 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-M'-cargo 13, 40 A42 Ac-KKKRK-PEG4-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 13, 39 A43 Ac-KKKRK-PEGs-K(cyclo[FfFGRGRQ])-PEGs-RF-M'-cargo 13, 39A44 Ac-KKRK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 1, 39No. Compound SEQ ID NOS:A45 Ac-KRK-PEG2-K(cyclo[FfFGRGRQ])-PEGs-RF-M'-cargo 39 A46 Ac-RK-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 39 A47 Ac-RF-PEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-M'-cargo 39A48 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-M'-cargo 13, 40Table 4B.SEQ IDNo. CompoundNOS:A49 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFE-M'-cargo 13, 40

[0231] In embodiments, a compound is selected from Table 4A or 4B In embodiments, a compound is selected from Table 4A or 4B where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 4A. In embodiments, a compound is selected from Table 4A where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 4A where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG- CAG-CAG-CAG-CAG-3 \ In embodiments, a compound is selected from Table 4B In embodiments, a compound is selected from Table 4B where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 4B where M' is absent and cargo is a PMO of the sequence 5 ’ -CAG-CAG-C AG-CAG-C AG-CAG-C AG-3 ’.

[0232] In embodiments, the compound of Formula III may be of Formula B:Formula B:H-N! cargo (AA3) y O / |3 ^ s3 'm10Formula Bor a pharmaceutically acceptable salt thereof,where a3 is 1, R40is H or CH3, and R20, AA1, al, xl, j 1, wl, y, n, Rl, R2, R3, R4, R5, R6, R7, x2, j2, AA3, x3, j 3, ml, M', and cargo are defined herein.

[0233] In embodiments R40 is H. In embodiments R40is CH3 When R40is CH3, the amino acid of the cCPP having the R2side chain can is N-methylated (e.g., N-methylated phenylalanine (f(N-me) or F(N-me)), N-methylated glycine (GfN-me)), and the like).

[0234] Examples of compounds of Formula B include those listed in Table 5A, Table 5B, and Table 5C where Ac is -C(O)CH3; the cCPP is written as JA(cyclo[XAXBXcXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue, “miniPEGb” indicates -(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates -(CH2-CH2-O)#-CH2-CO- or -(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M’ can be absent (i.e., ml is 0) or any M' described herein (i.e., when ml is 1); and cargo can be any ASO described herein. In embodiments, the cargo is a PMO. In embodiments, the cargo is a PNA. In embodiments of the compounds of Table5A, Table 5B, and Table 5C, each instance of “PEG2” refers to –(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEGz”) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 5A, Table 5B, and Table 5C, each instance of “PEG2” refers to –(CH2-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 5A.SEQ IDNo. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PEG2-M'-cargoBl (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bip-PEG2-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bta-PEG2-M'-cargoB2 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-niiniPEG2-R-Bta- 13, 40 miniPEG2-M'-cargo)Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-M'-cargoB3 87, 40 (e.g., Ac-RBRRBR-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-CO[PMO])Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFR-PEG4-M'-cargoB4 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFR-PEG4- 18, 40 M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoB5 (Ac-KKKRK-miniPEG2-K(cyc]o[FGFGRGRQ])-miniPEG2-RF-PEG4-M'- 13, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-M'-cargoB6 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-M'- 18, 39 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoB7 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-M’- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargoB8 13, 40 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEGs-RF-PEG4-M'-cargoB9 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-M'- 13, 39 cargo)Ac-KKKRK-PEG2-K([cyclo[FGFRHRHQ])-PEG2-RF-PEG4-M'-cargoBIO (Ac-KKKRK-miniPEG2-K([cyclo[FGFRHRHQ])-miniPEG2-RF-PEG4-M'- 13, 42 cargo)Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ]-PEG2-RF-PEG4-M'-cargo2, 40 Bll (Ac-KKFRK-miniPEG2-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-M'- cargo)Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ]-PEG2-RF-PEG4-M'-cargoB12 (Ac-KKKRK-miniPEG2-K(cyclo[FGRGFGRQ]-miniPEG2-RF-PEG4-M'- 13, 84cargo)SEQ I D No. CompoundNOS: Ac-KKKRK-PEG2-K(cyclo[FGFLRLRQ]-PEG2-RF-PEG4-M'-cargoB13 (Ac-KKKRK-miniPEG2-K(cyclo[FGFLRLRQ]-miniPEG2-RF-PEG4-M'- 13, 41 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFVRVRQ]-PEG2-RF-PEG4- M'-cargoB14 (Ac-KKKRK-miniPEG2-K(cyclo[FGFVRVRQ]-miniPEG2-RF-PEG4-M'- 13, 43 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoB15 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-M'- 13, 40 cargo)Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargoB16 (Ac-KKRK-miniPEG2-K(cyclo[FGFGRGRQp-miniPEG2-RF-PEG4-M'- 1, 40 cargo)Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargoB17 1, 40 (Ac-KKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-PEG2-M'-cargoB18 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-miniPEG2-M'- 13, 40 cargo)Ac-YArVRRrGPR-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-M'-cargoB19 (Ac-YArVRRrGPR-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 21, 39 M'-cargo)Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEG8-M'-cargoB20 40, 18 (Ac-K(cyclo[FGFGRGRQ])-miniPEG2-PKKKRKV-PEG8-M'-cargo)B21 Ac-KKKRK-PEG2-K(cyclo[FGFLRLRQ]-PEG2-RF-PEG4-M'-cargo 13, 41 B22 Ac-TKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 9, 40 B23 Ac-KKTRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 8, 40 B24 Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-M'-cargo 21, 40 B25 Ac-KKKRK-PEG2-K(cyclo[G-f(N-me)-FGrGrQ])-PEG2-RG-PEG4-M'-cargo 13, 55 B25.1 Ac-KKKRK-PEG2-K(cyclo[G-f(N-me)-FGrGrQ])-PEG2-RF-PEG4-M,-cargo 13, 55 B26 Ac-KKKRK-PEG2-K(cyclo[Gf-Nal-GrGrQ])-PEG2-RF-PEG4-M'-cargo 13, 56 B27 Ac-KKKRK-PEG2-K(cyclo[GyYGrGrQ])-PEG2-RF-PEG4-M'-cargo 13, 58 B28 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-PEG4-M,-cargo 13, 40 B29 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG2-M'-cargo 13, 4013, 40 B30 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-PEG4-M'-cargo 13, 40 B31 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFR-PEG4-M'-cargo 13, 40 B32 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-R-PEG4-M'-cargo 13, 40 B33 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bip-R-PEG4-M,-cargo 13, 40 B34 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PEG4-M'-cargo 13, 40 B35 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG8-M'-cargo 13, 40 B36 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-M'-cargo 13, 40B37 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(3-Pyr)-PEG4-M'-cargo 13, 40SEQ I D No. CompoundNOS: B38 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(2-Pyr)-PEG4-M'-cargo 13, 40 B39 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-(4-Pyr)-PEG4-M'-cargo 13, 40 B40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Phe(3-CN)-PEG4-M'-cargo 13, 40B41 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Trp(5-F)-PEG4-M'-cargo 13, 40B42 B42 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Tyr(Ph)-PEG4-M'-cargo 13, 40 B43 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-HoArg-Bip-PEG4-M'-cargo 13, 40B44 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-rf-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-R(me)-F(me)-PEG4-M!- B45 13, 40 cargoAc-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEG8-R-(4-Pyr)-PEG4-Nal-M'- B46 13, 40 cargoB47 Ac-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEG8-R-Nal-PEG4-F-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ])-PEG2-RF-PEG4- B48 13, 46 M'-cargoAc-KKKRK-PEG2-K(cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ])-PEG2-R-Bip- B49 13, 46 PEG4-M'-cargoB50 Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 13, 40 B51 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bta-PEG4-M'-cargo 13, 40 B52 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RFRF-PEG4-M'-cargo 13, 40, 33 B53 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RRFF-PEG4-M'-cargo 13, 40, 86 B54 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-M'-cargo 40 B55 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KFKF-PEG4-M'-cargo 40, 32 B56 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-EF-PEG4-M'-cargo 13, 40 B57 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Nal-PEG4-M'-cargo 13, 40 B58 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Bip-PEG4-M'-cargo 13, 40 B59 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 1, 40 B60 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FGR-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(Phe(4-CN)-G-Phe(4-CN)-GRGRQ)-PEG2-RF-PEG4- B61M'-cargo 13, 59 B62 Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 13, 40 B63 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-K-PEG4-M'-cargo 1, 40 B64 Ac-KKRK-PEG2-K(cyclo[FGFGRrRQ])-PEG2-RF-PEG4-M'-cargo 1, 53 B65 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-F(l)-PEG4-M'-cargo 13, 40 B66 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FR-PEG4-M'-cargo 13, 40 B67 Ac-KKKRKR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-F-PEG4-M'-cargo 17, 40 B68 Ac-KKKRKF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG4-M'-cargo 16, 40B69 Ac-KKKRK-PEG2-K(cyclo[GFRGFRGQ])-PEG2-RF-PEG4-M'-cargo 13, 57SEQ ID No. CompoundNOS: B70 Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])-PEG2-RF-PEG4-M'-cargo 13, 84 B71 Ac-KKKRK-PEG2-K(cyclo[FFGRRGQ])-PEG2-RF-PEG4-M'-cargo 13, 49 B72 Ac-KRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 40 B73 Ac-RK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 40 B74 Ac-RF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 40 B75 Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 1, 40 B76 Ac-KGKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 3, 40 B77 Ac-KKGRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 4, 40 B78 Ac-KKKGK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 5, 40 B79 Ac-KKRKG-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 6, 40 B80 Ac-KKRKK-PEG2-K(cyclo[FGFG-Cit-GRQ])-PEG2-RF-PEG4-M'-cargo 7, 51 B81 Ac-KKRKK-PEG2-K(cyclo[FGFGRG-Cit-Q])-PEG2-RF-PEG4-M'-cargo 7, 52 B82 Ac-KKRKK-PEG2-K(cyclo[AGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 7, 47 B83 Ac-KKRKK-PEG2-K(cyclo[FGAGRGRQ])-PEG2-RF-PEG4-M'-cargo 7, 50 B84 Ac-KKKGK-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG4-M'-cargo 5, 39 B85 Ac-RF-PEG2-K(cyclo[FFFGRGRQ])-PEG2-RF-PEG4-M'-cargo 48 B86 Ac-KKFRK-PEG2-K(cyclo[FFFGRGRQ])-PEG2-RF-PEG4-M'-cargo 2, 48 B87 Ac-KKKRK-PEG2-K(cyclo[FRFRFRFQ])-PEG2-RF-PEG4-M'-cargo 13, 54 B88 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-SF-PEG4-M'-cargo 13, 40 B89 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RL-PEG4-M'-cargo 13, 40 B90 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RY-PEG4-M'-cargo 13, 40 B91 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RW-PEG4-M'-cargo 13, 40 B92 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Cit-F-PEG4-M'-cargo 13, 40 B93 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RGF-PEG4-M'-cargo 13, 40 B94 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RPF-PEG4-M'-cargo 13, 40 B95 Ac-KKKRK-PEG2-K(cyclo[FGF-G(N-me)-RGRQ])-PEG2-RPF-PEG4-M'-cargo 13, 60 B96 Ac-KKKRK-PEG2-K(cyclo[F-G(N-me)-FGRGRQ])-PEG2-RPF-PEG4-M'-cargo 13, 61 B97 Ac-KKKRK-PEG2-K(cyclo[FAFARGRQ])-PEG2-RF-PEG4-M'-cargo 13, 62 B98 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Agp-Bip-PEG4-M'-cargo 13, 40 B99 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])- PEG2-Agp-F-PEG4-M'-cargo 13, 40 B100 Ac-KKKRK-PEG2-K(cyclo[FGFG-Agp-G-Agp-Q])-PEG2-RF-PEG4-M'-cargo 13, 40Table SB.SEQ IDNo. CompoundNOS: B101 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-M'-cargo 13, 63 B102 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG2-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Phg-PEG4-M'-cargo B103 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-Hph-PEG4-M'-cargo B104 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-Pcpa-F-PEG4-M'- B105 cargo 13, 40 B106 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-rf-PEG4-M'-cargo 13, 40 B107 Ac-kkkrk-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[Pcpa-G-Pcpa-GRGRQ])-PEG2-RF-PEG4- B108 M'-cargo 12, 40B109 Ac-RFGRK-PEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-M'-cargo 13, 64Table SC.SEQ IDNo. CompoundNOS:B110 Ac-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-M'-cargo 24, 40

[0235] In embodiments, a compound is selected from Table 5A, 5B, or 5C. In embodiments, a compound is selected from Table 5A, 5B, or 5C where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 5A. In embodiments, a compound is selected from Table 5A where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 5A where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG- CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 5B. In embodiments, a compound is selected from Table 5B where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 5B where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 5C. In embodiments, a compound is selected from Table 50 where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 50 where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-C AG-C AG-CAG-CAG-CAG-3’

[0236] In embodiments, the compound of Formula III may be of Formula C:Formula C:H <3 (AA1|~N > cargo ' tv R 1•‘Wx<**3cx30 \ -y NH CM< h O 0R£<\Hnfvy -Z \ V OO ^4 or a pharmaceutically acceptable salt thereof,where a3 and a4 are 1 and R20, AA1, al, xl, j 1, wl, y, n, R1, R2, R3, R4, R5, R6, R7, x2, j2, AA3, x3, j3, AA4, ml, M', and cargo are defined herein.

[0237] Examples of compounds of Formula C include those listed in Table 6A and Table 6B where Ac is -C(O)CFb; the cCPP is written as JA(cyclo[XAXBXCXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGz” indicates ~(CH2-CH2-O)2-CH2-CO-; “PEG ” indicates --(CH2-CH2- O)#-CH2-CO- or -(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' can be absent (i.e., l is 0) or any M' described herein (i.e., when ml is 1), and cargo can be any ASO described herein. In embodiments, the cargo is a PMO. In embodiments, the cargo is a PNA. In embodiments of the compounds of Table 6A and Table 6B, each instance of “PEG2” refers to ~(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEG?”) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 6A and Table 6B, each instance of “PEG2” refers to (CH2-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 6A.SEQ IDNo. CompoundNOS:Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-rf-PEG4-Bip-M'-cargoCl (Ac-KKKRK-mimPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-rf-PEG4-Bip-M'- 13, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG2-Bip-M'-cargoC2 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-miniPEG2- 18, 39 Bip-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargoC3 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEGi-F-M'-cargoC4 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-F-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-R-M'-cargoC5 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-R-M'- 13, 40 cargo)Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ])-PEG2-RF-PEG4-F-M'-cargoC6 (e g, Ac-KKKRK-miniPEG2-K(cyclo[FGFRRRRQ]-miniPEG2-RF-PEG4-F- 13, 81 CO[PMO|)Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargoC7 2, 40 Ac-KKFRK-miniPEG2-K(cyclo[FGFGRGRQ]-miniPEG2-RF-PEG4-F-M'-cargoAc-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargoC8 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F-M'- 18, 40 cargo)Ac-RBRRBR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bta-M'-cargoC9 (Ac-RBRRBR-miniPECh-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bta-M'- 20, 40 cargo)Ac-KKKRK-PEG2-K([cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Nal-M’-cargoC10 (Ac-KKKRK-miniPEG2-K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Nal-M'- 13, 40 cargo)Ac-KKKRK.-PEG2-K([cyclo[FGFGRGRQ])-PEGs-RF-PEG4-Nal-M’-cargoCll (Ac-KKKRK-miniPEG2-K([cyclo[FGFGRGRQ])-PEG8-RF-PEG4-Nal-M'- 13, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FfFGRGRQ])-PEG2-RF-PEG2-Nal-M'-cargoC12 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-miniPEG2- 18, 39 Nal-M' -cargo)Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-KF-PEG4-Bip-M'-cargoC13 (Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-Bip-M'- 13, 40cargo)SEQ ID No. CompoundNOS:Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargoC14 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F-M!- 18, 40 cargo)Ac-PKKKRKV-PEG2-K(cyclo[FflFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargoC15 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-Bip- 18, 39 M'-cargo)Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-PEG2-(2-Nal)- M'-cargoCl 6 18, 40 (Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-miniPEG2- (2-Nar)-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FfFGRGRQ])-PEGi2-(2-Nal)-PEG2-(2-Nal)-M'- cargoCl 7 13, 39 (Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEGi2-(2-Nal]-miniPEG2-(2- Nal)-M'-cargo)Ac-KKKRK-PEG2-K(cyclo[FfFGRGRQ])-PEGi2-Bip-PEG2-Bip-M'-cargoC18 (Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEGi2-Bip-miniPEG2-Bip-M'- 13, 39 cargo)Ac-RBRRBR-K(cyc]o[FfFGRGRQ])-PEGi2-Nal-PEG2-Nal-M'-cargoC19 87, 39 (Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEGi2-Nal-miniPEG2-Nal-M'-cargo)Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4-Nal-PEG2-Nal-M'-cargoC20 87, 40 (Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4-Nal-miniPEG2-Nal-M'-cargo)C21 Ac-KKKRK-PEG2-K(cyclo[FFFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 13, 48 C22 Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ])-PEG2-RF-PEG4-F-M'-cargo 13, 81 C23 Ac-RF-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 40 C24 Ac-KRK-PEG2-K(cyclorFGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 40C25 Ac-KFK-PEG2-K(cyclorFGFGRGRQ])-PEG2-RF-PEG4-F-M'-cargo 40 Table 6B.SEQ IDNo. CompoundNOS: C26 Ac-KKKHH-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo 15, 40 Ac-K(me)-K(me)-K(me)-R(me)-K(me)-PEG2-K(cyclo[FGFGRGRQ])- C27 15, 40 PEG2-RF-PEG4-Bip-M'-cargoAc-KBKBKBRBK-PEG2~K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip- C28 14, 40 M' -cargoC29 Ac-KKKRK-PEG2-K(cyclo[GFRGFRGQ])-PEG2-RF-PEG4-Bip-M’-cargo 23, 40 C30 Ac-KKKRK-PEG2-K(cvclo[GRFGRFGQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 57 Ac-RFKKRFK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'- C31 13, 66 cargoAc-YArVRRrGPR-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip- C32 24, 40 M'-cargoC33 Ac-KKKRK-PEG2-K(cyclo[RFGGRFGQ])-PEG2-RF-PEG4-Bip-M'-cargo 21, 40SEQ ID No. CompoundNOS: Ac-(N(k))-(N(k))-(N(k))-(N(Arg))-(N(k))-PEG2-K(cyclo[FGFGRGRQ])- C34 13, 67 PEG2-RF-PEG4-Bip-M ’-cargoC35 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo 25, 40 Ac-(N(Arg))-B-(N(Arg))-(N(Arg))-B-(N(Arg))-K(cyclo[FGFGRGRQ])- C36 13, 40 PEG2-RF-PEG4-Bip-M'-cargoAc-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FRF-PEG4-Bip-M'- C37 26, 40 cargoC38 Ac-KKKRK-PEG2-K(cyclo[GFFGRGRQ])-PEG2-RF-PEG4-Bip-M'-cargo 13, 40

[0238] In embodiments, a compound is selected from Table 6A or 6B. In embodiments, a compound is selected from Table 6A or 6B where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 6A. In embodiments, a compound is selected from Table 6A where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 6A where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3’. In embodiments, a compound is selected from Table 6B. In embodiments, a compound is selected from Table 6B where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 5B where M' is absent and cargo is a PMO of the sequence 5 ’ -C AG-CAG-CAG-CAG-C AG-CAG-CAG-3 ’.

[0239] In embodiments, the compound of Formula 111 may be of Formula D:Formula D:H / H 42 oFor uh Dor a pharmaceutically acceptable salt thereof,where a2 and a3 are 1 and R20, AA1, al, xl, j1, wl, y, n, R1, R2, R3, R4, R5, R6, R7, x2, j2, AA3, ml, M', and cargo are defined herein.

[0240] Examples of compounds of Formula D include those listed in Table 7 where Ac is -C(O)CHs; the cCPP is written as JA(cyclo[XAXBXcXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGz” indicates -(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates -(CH2-CH2-O)#-CH2-CO- or (CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' can be absent (i e., ml is 0) or any M' described herein (i e., when ml is 1); and cargo can be any ASO described herein. In embodiments, the cargo is a PMO, In embodiments, the cargo is a PNA. In embodiments of the compounds of Table 7, each instance of “PEG2” refers to ~(CH2-CH2-O)2-CH2-CO- (i.e., “miniPEG2”) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 7, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to ”(CH -CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 7.SEQ IDNo.Compound NOS: DI Ac-K(cyclo[FGFGRGRQ])-KKKRK-PEGi2-(2-Nal)-M'-cargo 40, 13 D2 Ac-KKK-K(cyclo[FGFGRGRQ])-RK-PEG12-(2-Nal)-M'-cargo 89, 40 Ac-KKK-PEG2-K(cyclo[FGFGRGRQ])-RK-PEGj2-(2-Nal)-M'-cargoD3 (Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-RK-PEGi2-(2-Nal)-M'- 40cargo)

[0241] In embodiments, a compound is selected from Table 7 In embodiments, a compound is selected from Table 7 where M' is absent and cargo is a PMO. In embodiments, a compound is selected from Table 7 where M' is absent and cargo is a PMO of the sequence 5’-CAG-CAG-CAG-CAG-C AG-C AG-CAG-3 ’.

[0242] In embodiments, the compound of Formula III may be of Formula E:Formula E:Formula Eor a pharmaceutically acceptable salt thereof,where a2 is 1 and R20, AA1, al, xl, j1, wl, y, n, R1, R2, R3, R4, R5, R6, R7, AA2, x2, j2, ml, M', and cargo are defined herein.

[0243] Examples of compounds of Formula E include those listed in Table 8 where Ac is -C(O)CI-l3, the cCPP is written as JA(cyclo[XAXBXcXDXEXFXGYAJ) where XA, XB, XC, XD, XE, XF, and XGare amino acid residues with side chains R1, R2, R3, R4, R5, R6, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEC ” indicates -(CH2-CH2-O)2-CH2-CO-; “PEG#” indicates ~(CH2-CH2-O)#-CH2-CO- or -(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' can be absent (i.e., ml is 0) or any M' described herein (i e., when ml is 1); and cargo can be any ASO described herein. In embodiments, the cargo is a PMO. In embodiments, the cargo is aPNA. In embodiments of the compounds of Table 8, each instance of “PEG?” refers to -(CFb-CIl2-O)2-CI l2-CO- (i.e., “miniPEG ”) and each instance of “PEG#” refers to --(CH2-CH2-O) - CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 8, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH -CH2-CO- and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 8.SEQ IDNo. CompoundNOS: Ac-PKKKRKV-PEG2-K(cyelo[FfFGRGRQ])-RF-PEG!-M'-cargoEl 18, 39 (Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-RF-PEG4-M'-cargo)E2 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-R-Bip-PEG8-M'-cargo 13, 40 E3 Ac-PKKKRKV-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG4-M'-cargo 13, 40 E4 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-RF-PEG4-M'-cargo 13, 40E5 Ac-KKKRK-PEG2-K(cyclo|FGFGRGRQ])-RF-PEG2-M'-cargo 13, 40

[0244] In embodiments, a compound is selected from Table 8. In embodiments, a compound is selected from Table 8 where M' is absent and cargo is a PMO In embodiments, a compound is selected from Table 8 where M' is absent and cargo is a PMO of the sequence 5 -CAG-CAG-C AG-C AG-CAG-CAG-C AG-3 ’

[0245] In embodiments, the compound of Formula IIII may be of Formula F:Formula F:■ H, 9H? / H O.. J... 03,. il.! V O;0 / WXs(AA3f N i M (M’i c.ai'go! O AHr%^o) *» < i VN3V 0< AM)H '• 4s mi t H k 'r> 0 / 0R1R'. ' N H... 0MR« yRzKp6X RH MN,i O^X^MH H A-p;N-~\RR5> ( QO' R4or a pharmaceutically acceptable salt thereof,where x4 is an integer from 1 to 14; j4 is integer from 1 to 4; R40is H or CH’, and R20, AA1, al, xl, j l, wl, y, n, R1, R2, R3, R4, R5, R6, R7, x2, j2, AA3, x3,j3, AA4, ml, M', and cargo are defined herein.

[0246] x4 is an integer from 1 to 14. x4 can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. x4 can be 2, 4, 6, 8, 10, or 12. x4 can be 2, 4, 8, or 12. x4 can be 2 x4 can be 4. x4 can be 6. x4 can be 8. x4 can be 12.

[0247] j4 can be integer from 1 to 4. 0. j4 can be 1. j4 can be 2. j4 can be 3. j4 can be 4.

[0248] Examples of compounds of Formula F include those listed in Table 9 where Ac is - C(O)CHs; the cCPP is written as JA(cyclo[XAXBXcXDXEXFXGYA]) where XA, XB, XC, XD, XE, Xr, and XGare amino acid residues with side chains R1, R2, R3, R4, R\ R°, and R7, respectively, YAis the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGz” indicates ~(CH2-CH2-O)2-CH -CO-; “PEG #” indicates ”(CH2-CH2-O)#-CH2-CO- or -(CH2-CH2-O)#-CH2-CH2-CO- where # indicates to the number of -CH2-CH2-O- units; M' can be absent (i.e., ml is 0) or any M' described herein (i.e., when ml is 1); and cargo can be any ASO described herein. In embodiments, the cargo is a PMO. In embodiments, the cargo is a PNA. In embodiments of the compounds of Table 9, each instance of “PEG2” refers to -(CH2- CH2-O)2-CH2-CO- (i.e., “miniPEG2,) and each instance of “PEG#” refers to -(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2. In embodiments of the compounds of Table 9, each instance of “PEG2” refers to -(CH2-CH2-O)2-CH2-CH2-CO- and each instance of “PEG#” refers to ”(CH2-CH2-O)#-CH2-CH2-CO- where # is an integer greater than 2.Table 9.SEQ IDNo. Compound NOS: F1 Ac-K(cyclo[FCjFGRGRQ])-PEG2-PKKKRKV-PEG8-RF-PEG4-M'-cargo 40, 18 F2 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-R-PEG2-F-PEG4-M'-cargo 13, 40 Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-Bip-PEG4-M'- F3 13, 40 cargoF4 Ac-K(cyclo[FGFGRGRQ])-PEG2-PKKKRKV-PEG8-RF-PEG4-M'-cargo 40, 18

[0249] In embodiments, a compound is selected from Table 9. In embodiments, a compound is selected from Table 9 where M' is absent and cargo is a PMO In embodiments, a compound is selected from Table 9 where M' is absent and cargo is a PMO of the sequence 5 -CAG-CAG-C AG-CAG-CAG-C AG-CAG-3 ’Pharmaceutical Compositions and Methods of Administration

[0250] The compounds of the present disclosure may be formulated into compositions suitable for in vivo applications. The compounds and / or compositions may be administered to a human patient that has, or is suspected of having, DM1.

[0251] In vivo application of the disclosed compounds, and compositions containing them, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the disclosed compounds can be formulated in a physiologically-or pharmaceutically-acceptable composition and administered by any suitable route known in the art including, for example, oral and parenteral routes of administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscul r, intraperitoneal, intrasternal, and intrathecal administration, such as by injection. Administration of the disclosed compounds or compositions can be a single administration, or at continuous or distinct intervals as can be readily determined by a person skilled in the art.

[0252] The compounds disclosed herein, and compositions comprising them, can also be administered utilizing liposome technology, slow-release capsules, implantable pumps, and biodegradable containers. These delivery? methods can, advantageously, provide a uniform dosageover an extended period of time. The compounds can also be administered in their salt derivative forms or crystalline forms.

[0253] The compounds disclosed herein can be formulated into pharmaceutical compositions according to known methods for preparing pharmaceutically acceptable compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example. Remington ’s Pharmaceutical Science by E. W. Martin (1995) describes formulations that can be used in connection with the disclosed methods. In general, the compounds disclosed herein can be formulated such that an effective amount of the compound is combined with a suitable carrier in order to facilitate effective administration of the compound. The compositions used can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, suppositories, injectable and infusible solutions, and sprays. The form depends on the intended mode of administration and therapeutic application. The compositions also include conventional pharmaceutically acceptable carriers and diluents which are known to those skilled in the art. Examples of carriers or diluents for use with the compounds include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents. To provide for the administration of such dosages for the desired therapeutic treatment, compositions disclosed herein can advantageously comprise between about 0.1% and 100% by weight of the total of one or more of the subject compounds based on the weight of the total composition including carrier or diluent.

[0254] Formulations suitable for administration include, for example, aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions, which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powder, granules, tablets, and the like. It should be understood that in addition to the ingredients particularly mentioned above, the compositions disclosed herein can include other agents conventional in the art having regard to the type of formulation in question.

[0255] Compounds and compositions disclosed herein, including pharmaceutically acceptable salts or prodrugs thereof, can be administered intravenously, intramuscularly, or intraperitoneally by infusion or injection. Solutions of the active agent or its salts can be prepared in water, optionally mixed with a nontoxic surfactant Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[0256] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the appropriate particl e size in the case of dispersions or by the use of surfactants. Optionally, the prevention of the action of microorganisms can be brought about by various other antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents may be included, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[0257] Sterile injectable solutions are prepared by incorporating a compound and / or agent disclosed herein in the appropriate amount in the appropriate solvent with various other ingredients enumerated above, as appropriate, followed by filter sterilization In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0258] Useful dosages of the compounds and agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art.

[0259] The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days

[0260] Also disclosed are pharmaceutical compositions that comprise a compound disclosed herein in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of a compound are disclosed herein. The dose administered to a patient, particularly a human, should be sufficient to achieve a therapeutic response in the patient over a reasonable time frame, without lethal toxicity, and causing no more than an acceptable level of side effects or morbidity One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition (health) of the subject, the body weight of the subject, kind of concurrent treatment, if any, frequency of treatment, therapeutic ratio, as well as the severity and stage of the pathological condition.

[0261] Also disclosed are kits that comprise a compound disclosed herein and / or pharmaceutical compositions containing the same, in one or more containers The disclosed kits can optionally include pharmaceutically acceptable carriers and / or diluents. In one embodiment, a kit includes one or more other components, adjuncts, or adjuvants as described herein. In one embodiment, a kit includes instructions or packaging materials that describe how to administer a compound or composition of the kit. Containers of the kit can be of any suitable material, for example glass, plastic, metal, and the like, and of any suitable size, shape, or configuration. In one embodiment, a compound and / or agent disclosed herein is provided in the kit as a solid, such as a tablet, pill, or powder form. In another embodiment, a compound and / or agent disclosed herein is provided in the kit as a liquid or solution. In one embodiment, the kit comprises an ampoule or syringe containing a compound and / or agent disclosed herein in liquid or solution form.

[0262] In embodiments, the compound and / or composition of the disclosure is administered to a subject at a dose of 0.1 mg / kg to 50 mg / kg. The subject may have been diagnosed with DM1.Certain Definitions

[0263] The type and origin of the molecule are not limited by the case and / or typeface (e.g., bold, italics, etc.). A specific name of gene, transcript, or protein may be denoted as unitalicized and upper case, italicized and upper case, unitalicized and upper case, or unitalicized and lower case. The specific type and origin of the molecule are to be understood in the context of the use of the stated molecule.

[0264] In the preceding description and following claims, the term “and / or” means one or all of the listed elements or a combination of any two or more of the listed elements; the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0265] As used herein, “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” or the like are used in their open-ended inclusive sense, and generally mean “include, but not limited to,” “includes, but not limited to,” or “including, but not limited to.” Further, wherever embodiments are described herein with the language “have,” “has,” “having,” “include,” “includes,” “including,” “comprise,” “comprises,” “comprising” and the like, otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. The term “consisting of’ means including, and limited to, that which follows the phrase “consisting of.” That is, “consisting of’ indicates that the listed elements are required or mandatory, and that no other elements may be present The term “consisting essentially of” indicates that any elements listed after the phrase are included, and that other elements than those listed may be included provided that those elements do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements.

[0266] In the preceding description, particular embodiments may be described in isolation for clarity. Reference throughout this specification to “embodiments,” “one embodiment,” “an embodiment,” “certain embodiments,” “one or more embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described inconnection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments. Thus, features described in the context of one embodiment may be combined with features described in the context of a different embodiment except where the features are necessarily mutually exclusive.

[0267] In several places throughout the above description, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

[0268] As used, “aromatic” refers to an unsaturated cyclic molecule having 4n + 2 electrons, wherein n is any integer. “Heteroaromatic,” defined below, is a subset of aromatic. Examples of aromatic amino acids include phenylalanine and naphthylalanine. The term “non-aromatic” or “not-aromatic” refers to any molecule that does not fall within the definition of aromatic. For example, any linear, branched or cyclic molecule which does not fall within the definition of aromatic is non-aromatic. Examples of non-aromatic amino acids include, but are not limited to, glycine and citrulline.

[0269] As used herein, the symbol “* ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which y’C V — | — is not depicted as being attached to the point of attachment bond. For example, “I ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound CH3-R3, wherein RJis H or “ XY-I-? ” infers that when RJis “XY’, the point of attachment bond is the same bond as the bond by which R3is depicted as being bonded to CH3.

[0270] As used herein, by a “subject” is meant a human patient.

[0271] As used herein, “treat,” “treating,” “treatment” and variants thereof, refers to any administration of the disclosed compounds that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms or features of a disease as described herein. In reference to a patient, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associ ted disease, pathological condition, or disorder.

[0272] “Peptide” refers to a sequence of amino acid residues without regard to the length of the sequence. Therefore, the term “peptide” refers to any amino acid sequence having at least two amino acids.

[0273] The term “pharmaceutically acceptable” refers to those compoun s, salts of compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and / or animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0274] A number of embodiments of the disclosure have been described. Neverthel ess, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Other embodiments are within the scope of the following claims.

[0275] All publications, patents and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications, patents and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.EXAMPLES

[0276] The disclosure is illustrated by the following examples It is to be understood that the particular examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention as set forth herein.Example 1: Compound Synthesis

[0277] Delivery construct-PMO conjugates can be synthesized based on well-known procedures in the art as well as analogous to the general procedure outlined below.

[0278] Definitions and acryonyms used in the Examples include:

[0279] DMF: Dimethylformamide,

[0280] DCM: Dichloromethane,

[0281] Fmoc: Fluorenylmethoxycarbonyl,

[0282] Fmoc-PEG8-OH: Fmoc-NH-PEG8-CH2CH2COOH,

[0283] DMAP: 4-(Dimethylamino)pyridine,

[0284] DIC: N,N-Diisopropylcarbodiimide,

[0285] OxymaPure: Ethyl cyano(hydroxyimino)acetate,

[0286] CTC: 2 -chlorotrityl chloride,

[0287] PyOxim: [Ethyl cyano(hydroxyimino)acetato-O2]tri-l-pyrrolidinylphosphonium hexafluorophosphate,

[0288] HATU: O-(7- / \zabenzotriazol-l-yl)-N, N, N’, N’-tetramethyluronium hexafluorophosphate,

[0289] MeOH: Methanol,

[0290] DIPEA: N,N-Diisopropylethylamine,

[0291] DCBC: 2,5-Dichlorobenzoyl chloride,

[0292] DBU:l,8-Diazabicyclo[5.4.0]undec-7-ene,

[0293] NMM: N-Methylmorpholine,

[0294] DIPEA: N, N-Diisopropylethylamine,

[0295] IPA: Isopropyl alcohol,

[0296] NMP: N-Methyl-2-pyrrolidone,

[0297] NEM: N-Ethylmorpholine,

[0298] NMM: 4-Methylmorpholine,

[0299] ACN: Acetonitrile,

[0300] TFA: 2,2,2-Trifluoroacetic acid,

[0301] TIPS: Triisopropylsilane,

[0302] HO At: Hydroxy-7-azabenzotriazole,

[0303] Gly: Glycine,

[0304] Arg: Arginine,

[0305] SDDC: Sodium diethyldithiocarbamate trihydrate,

[0306] HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol,

[0307] MBTE: Methyl tert-butyl ether,

[0308] Lys(Dde): N-α-Fmoc-N-ε-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl-L-lysine,

[0309] AEEA 2-[2-[2-(Amino)ethyoxy]ethoxy]acetic acid also called “miniPEG”,

[0310] Val: Valine,

[0311] Arg: Arginine,

[0312] Lys(TFA): Trifluoroacetyl-protected lysine,

[0313] Pro: Proline,

[0314] Ac: Acetyl,

[0315] SPPS: Solid-phase peptide synthesis,

[0316] UPLC: Ultra High-Performance Liquid Chromatography,

[0317] MALDI-MS: Matrix- Assisted Laser Desorption Ionization Mass Spectrometry,

[0318] LC-MS: Liquid Chromatography Mass Spectrometry,

[0319] RCF:Relative Centrifugal Force,

[0320] ACN: Acetonitrile,

[0321] CEX: Cation Exchange Chromatography,

[0322] DIPEA: N, N-Diisopropylethylamine,

[0323] DMSO: Dimethyl sulfoxide,

[0324] EEV: Endosomal Escape Vehicle also called a delivery vehicle,

[0325] FA: Formic Acid,

[0326] HATU: O-(7-Azabenzotriazol- 1 -yl)-N, N, N’, N’ -tetramethyluronium hexafluorophosphate,

[0327] PMO: Phosphorodiamidate morpholino oligomer,

[0328] RPC: Reverse phase chromatography,

[0329] SCX: Strong cation exchange,

[0330] TFA: 2,2,2-Trifluoroacetic acid,

[0331] Resin Bed Volume: The volume that swelled, settled resin occupies inside of a container.

[0332] Synthesis of Ac-KKKRK-miniPEG2-K(cycIo[FGFGRGRQ])-PEG«-R-Bip- 3'-GAC- GAC-GAC-GAC-GAC-GAC-GAC-5' (Ac-KKKRK-nimiPEG2-K(cyclo[FGFGRGRQ])- PEGs-R-Bip-[CAG]7: see FIG. 6C for the structure)

[0333] Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-[CAG]7 was synthesized according to scheme shown across FIGS. 5A, 5B, and 5C.. In Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEGs-R-Bip-[CAG]7, “miniPEG2” refers to -(CH2-CH2-O)2-CH2-CO-and “PEG8” refers to -(CH2-CH2-O)8-CH2-CH2-CO-).Resin loading and sequence elongation (FIG. 6A)

[0334] CTC resin (5.0 mmol, 0.55 mmol / g, 9.09 g) was weighed and placed inside of a glass peptide synthesis vessel. Anhydrous DCM was added and the resin was allowed to swell for 60 minutes in an incubated shaker set to 25 °C and mixed at 175 rpm. The resin was drained, Fmoc-Bip-OH (2.31 g, 5.0 mmol, 1.00 eq), DIEA (4.0 eq) and MeOH (250 mL) were added and the reaction was was mixed for 30 minutes at 150 rpm. Resin was drained and washed thrice with DMF.

[0335] CTC resin, loaded with Fmoc-Bip-OH was placed inside a glass peptide synthesis vessel. DMF was added and the resin was allowed to swell for 60 minutes in an incubated shaker set to 25 °C and mixed at 175 rpm. The resin was drained and 20% piperidine in DMF solution was added and the mixture was placed in an incubated shaker set to 25 °C and reacted for 20 minutes at 175 rpm. After 20 minutes, the resin was drained, and washed three times each with the following solvents (in order): DMF, DCM, and DMF. Fresh 20% piperidine in DMF was added to the resin and the process was repeated.

[0336] The peptide was elongated using SPPS by coupling the amino acids from C-terminus to N-terminus. The sequence of couplings from Fmoc-Bip-OH is Fmoc-Arg(Pbf)-OH (3.00 eq), Fmoc-PEG8-OH (Fmoc-(CH2-CH2-O)8-CH2-CH2-C(O)OH; 8.00 eq), Dde-Lys(Fmoc)-OH (3.00 eq), Fmoc-Glu(OAll)-OH (3.00 eq), Fmoc-Gly-Arg(Pbf)-OH (2.00 eq), Fmoc- Arg(Pbf)-OH (3.00 eq), Fmoc-Gly-OH (3.00 eq), Fmoc-Phe-OH (3.00 eq), Fmoc-Gly-OH (3.00 eq), Fmoc-Phe-OH (3.00 eq).

[0337] A vial was charged with 3-8 equiv. of the desired Fmoc Amino Acid and 3 equiv. of OxymaPure, DMF was added to the vial followed by 3.3 equiv. of DIC. The mixture was allowed to stand at room temperature for 10-20 minutes. The pre-activated Fmoc Amino Acid solution was added to swelled, drained resin. DMF was added to bring the total reaction volume to be 6 resin bed volumes and the mixture was shaken at room temperature for 3-8h, using an incubated shaker set to 25 °C and 175 rpm. The resin was drained and washed five times eachwith the following solvents (in order): DMF, DCM and DMF. The deprotection / coupling sequence was repeated until the coupling sequences was completed.Deallylation and cyclization (FIG. 6B)

[0338] The resin containing the peptide was suspended in DCM and swelled for 30 minutes. The resin was drained and resuspended in fresh DCM, 10 eq. of phenylsilane and 0.2 eq. of Pd(PPh3)4 was added and the reaction vessel was mixed in a shaker at 150 rpm set to 25 °C for 4 hours. The resin was drained and was washed five times each with DCM and DMF. The resin was resuspended in DMF and 0.8 eq. of SDDC was added and the reaction was shaken for 10 minutes at room temperature. The resin was drained, and resuspended in fresh DMF. 0.8 eq. of SDDC rvere added and mixed for 10 minutes, this step was repeated 2 more times for a total of 4 SDDC treatments to remove any residual Pd. Finally, the resin was washed 5 times with DMF and 5 times with DCM.

[0339] The resin was drained and 20% piperidine in DMF solution was then added and the mixture was placed in an incubated shaker set to 25 °C and reacted for 15 minutes at 175 rpm. After 15 minutes, the resin was drained, and washed three times each with the following solvents (in order): DMF, DCM, and DMF. Fresh 20% piperidine in DMF was added to the resin and the process was repeated two times.

[0340] The resin containing the peptide was swelled in a 1: 1 mixture of DCM and DMF for 60 minutes at room temperature. The resin was drained and then resuspended in fresh 1:1 DCM / DMF mixture (20 mL / mmol of peptide). Pyoxim (2 eq.), Oxyma (2 eq.), and DIPEA (3 eq.) were added and mixed in a shaker at 150 rpm set to 25 °C for 3 hours. The resin was drained, and washed washed 5 times with DMF and DCM. The resin was then washed 2 times with IPA and MTBE and dried.

[0341] 3% NH2NH2 / DMF and was added to the resin and the reaction was allowed to stand for 30 min, The resin was drained and the washed five times each with the following solvents (in order): DMF, DCM and DMF. The resin was dried and taken futher for sequence elaboration. Sequence elongation to synthesize protected EEVs

[0342] The sequence of couplings from resin loaded peptide is Fmoc-miniPEG2-OH ( AEEA, Fmoc-(CH2-CH2-O)8-CH2-C(O)OH, 3.00 eq), Fmoc-Lys(TFA)-OH (3.00 eq), Fmoc- Arg(Pbf)- OH (3.00 eq), Lys(TFA)-OH (3.00 eq), Lys(TFA)-OH (3.00 eq), Lys(TFA)-OH (3.00 eq).

[0343] A vial was charged with 3 eq. of the desired Fmoc Amino Acid and 3 eq. of OxymaPure, DMF was added to the vial followed by 3.3 eq. of DIC The mixture was allowed to stand at room temperature for 10-20 minutes. The pre-activated Fmoc Amino Acid solution was added to swelled, drained resin. DMF was added to bring the total reaction volume to be 6 resin bed volumes and the mixture was shaken at room temperature for 3-8h, using an incubated shaker set to 25 °C and 175 rpm. The resin was drained and washed five times each with the following solvents (in order): DMF, DCM and DMF. The deprotection / coupling sequence was repeated until the coupling sequences was completed.

[0344] After final coupling and deprotection steps, a solution of 5% acetic anhydride and 10% DIPEA in DMF was added to resin. The reaction was mixed at room temperature for 45 minutes, using an incubated shaker set to 25 °C and 175 rpm. The resin was drained and washed five times each with the following solvents (in order): DMF, DCM and DMF.

[0345] The resin was drained. 95% TFA, 2.5% water, 2.5% TIPS (v / v%) was added and the vessel was mixed in a shaker at 150 rpm set to 25 °C for 45 minutes. The reaction was drianed into pre-cooled MTBE, the peptide / MTBE suspension was transferred to 50 mL conical tubes and spun in a centrifuge at 4000 rpm for 10 minutes. The MTBE was carefully decanted, and fresh MTBE was added and the suspension was mixed for 30 minutes in a shaker at 150 rpm set to 25 °C. After mixing, the peptide was again spun in a centrifuge at 4000 rpm for 10 minutes. The MTBE was decanted, and the process was repeated for a total of 5 times to yield crude material that was further purified by prep-HPLC (A: 0.075 % TFA in H2O, B: ACN) to give the final product (1.25 g, 96.7 % purity, 8.12% yield).Conjugation of EEV with PMO (FIG. 6C)

[0346] A 21-mer PMO antisense sequence for triplet repeat sequences (5'-CAGCAGCAGCAGCAGCAGCAG-3') otherwise known as [CAG]7(SEQ ID NO: 76) was used. The PMO sequence targeting CUG / CTG expanded repeats (5'-CAGCAGCAGCAGCAGCAGCAG-3' was purchased from a commercial souce. BeforeH0-? N N-. X0 _, o' NH N-^ )—x'«',™X™ / H, N N, O N-P-d \ -__. / \,}— - '■« M'?- \ / Z Q » O N-P-d / - / 6'. 5 I ' o S NHj N-( | HO—; I y= / i H2N — { N N N s \=:^ X. _ |, o N.^N,v.. < / N-P-N' N— ) — A, Y / “■■■'y" 6 ’’ HzN”? N. Q N-P-0 \..:::: / Y aNHSN — A HO— N HaN ■■■■(;' > w,0 O' N-P-N7N-V ' y,Ayz\ axH2N -(' N., d N-P-Q V- y..AITrA ~yo 0 N- P O \.' B conjugation the [CAG]7PMO had the structureThe EEV was conjugated to the 3 ’-end of the PMO through the C -terminal carboxyl group of the EEV.

[0347] The conjugation procedure is shown in FIG. 6C. Breifly, to a solution of [CAG]? PMO in DMSO was added 1.6 eq. of HATU (500 mM solution in DMSO), 1.6 eq of EEV (200 mg / mL solution of DMSO) and 5 eq. of N, N-diisopropylethylamine. The reaction was allowed to stir at 25°C for 3h. Upon completion of the reaction, 40 eq. of NaOH (320 mM solution in water) was added and the mixture was allowed to stir for 1 hr. Reaction was neutralized using 500 mM NaH2PO4to bring the pH to 7.

[0348] Delivery construct-PMO conjugates disclosed herein were synthesized based on well- known procedures in the art as well as analogous to the general procedure outlined above.

[0349] The PMO-peptide conjugates were purified on an ion exchange column (Source 30S, 390 ml) using a linear gradient of sodium phosphate buffer (25 mM, pH 7.0) containing 15% CH3CN. A sodium chloride solution (0.75 M ) containing 15% CH3CN was used to elute the conjugate from the column at a flow rate of 30 mL / min. The fractions containing the desired compound were combined and diluted with MQ water and purified using reverse phase HPLC (A: H2O, B: ACN) using a gradient comprised of an isocratic hold at 10% mobile phase B to push off peptide, followed by a steep gradient and then another isocratic hold at 50% B to elute the desired product. Desired product fractions were combined, frozen with liquid nitrogen, and lyophilized to afford peptide-PMO conjugate as a white powder The concentration of peptide-PMO was determined by the molar absorption of the conjugates at 265 nm in 0.1 N HCI solution.

[0350] The EEV-PMO conjugates shown in Tables 10A-10B were made using analogous procedures to those disclosed herein and well-known procedures in the art. In Tables 10A-10B, Ac is -C(O)CH3, the cCPP is written as JA(cyclo[XAXBXCXDXEXFXGYA]) where XA, XB, XC, XD, XE, XF, and XGare amino acid residue with the side chain R1, R2, R3, R4, R5, R6, and R7respectively, Y ' is the cCPP bridging amino acid residue, and JAis the bridging exocyclic amino acid residue; “miniPEGj” indicates ~(CH2-CH2-O) -CH -CO-; “PEG#’’ indicates --(CH2-CH2-O)#-CH2-CH2-CO- where # indicates a number of -CH2CH2O- units that is greater than 2, M' isabsent (i.e., ml is 0) or Ml where Ml iswhere #2 is the point of attachment to the cargo, y″ is 4, x3 is 4, and j3 is 2; and cargo is a PMO having the sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' ([CAG]7) (SEQ ID NO: 76) conjugated to the delivery construct at the 3' terminus.Table 10A.Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-PKKKRKV-miniPEG2- 18, 40, 1 K(cyclo[FGFGRGRQ])-PEGi2-[2-Nal]- 9846.27 9845.876 [CAG]7Ac-PKKKRK V-miniPEG2- 18, 40, 2 9872.32 9871.8 K(cyclo[FGFGRGRQ])-PEGi2-Bip-[CAG]7 76 Ac-K(cyclo[FGFGRGRQ])-KKKRK-PEGi2- 40, 13, 3 9504.88 9504.5(2-Nal)-[CAG]7 76 Ac-PKKKRKV-miniPEG2- 18, 81, 4 K(cyclo[FGFRRRRQ])-PEG12-(2-Nal)- 10044.55 10044.176 [CAG]7Ac-PKKKRK V-mini PEG2- 18, 40, 5 K(cyclo[FGFGRGRQ])-PEGi2-[2-Nal]- 10188.67 10188.276 miniPEG2-(2-Nal)-[CAG]7Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])- 6 9650.04 9649.3 40, 76 PEG12-RK-[2-Nal]-[CAG]7Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])- 7 9550.04 9649.6 40, 76 RK-PEG12-(2-Nal)-[CAG]7Ac-KK-miniPEG2-K(cyclo[FGFGRGRQ])- 40, 30, 8 9650.04 9649.3 PEGi2-KRK-(2-Nal)-[CAG]7 76 Ac-K-miniPEG2-K(cyclo[FGFGRGRQ])- 40, 34, 9 9650.04 9649.6 PEG12-KKRK-(2-Nal)-[CAG]776 Ac-K(cyclo[FGFGRGRQ])-PEGi2-KKKRK- 40, 37, 10 9504.88 9504.4(2-Nal)-[CAG]7 76 Ac-KKK-K(cyclo[FGFGRGRQ])-RK-PEGi2- 89, 40, 11 9504.88 9504.2(2-Nal)-[CAG]776 Ac-KKK-K(cyclo[FGFGRGRQ])-PEGt2-RK- 89, 40, 12 9504.88 9504.3(2-Nal)-[CAG]7 76 Ac-KKK-K(cyclo[FGFGRGRQ])-PEGi2-rk- 89, 40, 13 9504.88 9504.3(2-nal)-[CAG]776 Ac-K(cyclo[FGFGRGRQ])-PEGi2-kkkr-(2- 40, 31, 14 9376.71 9376.2nal)-[CAG]7 76 Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrrQ])- 10, 45, 15 10044.55 10044.6 PEGi2-dNal-[CAG]776 Ac-pkkkrkv-miniPEG2-k(cyclo[fGfrrrQ])- 10, 45, 16 10044.55 10044.5 PEGj2-Nal-[CAG]7 76 Ac-pkkkrkv-miniPEG2-k(cyclo[fffrrrrQ])- 10, 82, 17 10134.67 10134PEGi2-dNal-[CAG]7 76Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-pkkkrkv-miniPEG2- 10, 81, 18 10044.55 10044.6 k(cyclo[FGFRRRRQ])-PEGi2-dNal-[CAG]7 76 Ac-pkkkrkv-miniPEG2-k( cyclo[fGfGrGrQ] )- 10, 83, 19 9846.28 9846.3 PEG12-dNal-[CAG]776 Ac-PKKKRKV-miniPEG2- 18, 40, 20 K(cyclo[FGFGRGRQ])-PEGi2-Bip-BRBRB- 10397.93 10397.435, 76 [CAG]7Ac-KKKRK-miniPEG2- 13, 39, 21 K(cyclo[FiFGRGRQ])-PEGi2-(2-Nal)- 10082.55 1008276 miniPEG2-(2-Nal)-[CAG]7Ac-KKKRK-miniPEG2- 13, 39, 22 K(cyclo[FfFGRGRQ])-PEGi2-BiP-miniPEG2- 10134.62 10134.676 Bip-[CAG]7Ac-KKKRK-mini PEG2- 13, 40, 23 K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 10143.6 10143.476 M1-[CAG]724 Ac-PKKKRKV-miniPEG2- 18, 39, (FIGS. 4A K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 9835.27 9833.8676 and 5) [CAG]7Ac-PKKKRKV-miniPEG2- 25 (FIGS. 18, 39,K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 10058.54 10058.2 4B and 5) 76Bip-[CAG]7Ac-PKKKRKV-miniPEG2- 18, 39, 26 K(cyclo[FfFGRGRQ])-nuniPEG2-RF- 9956.41 9955.776 miniPEG2-Bip-[CAG]727 Ac-KKKRK-miniPEG2- 13, 40, (FIGS. 4C K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9772.17 9771.876 and 5) Bip-[CAG]728 (FIGS. Ac-KKKRK-mini PEG2- 13, 40,9656.05 9655.44D and 5) K(cyclo[FGFGRGRQ])-PEG8-R-Bip-[CAG]7 76 29Ac-KKKRK-mi ni PEG2- 13, 40, (FIGS. 4E 9579.95 9579.2K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]776 and 5)Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEGi2- Nal-PEG2-Nal-[CAG]787, 39, 30 10035.42 10034.46(Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEG12- 76 Nal-miniPEG2-Nal-[ C AG]?)31 (FIGS. Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG4- 87, 40,9592.87 9592.44F and 5) Nal-miniPEG2-Nal-[CAG]7 76 32 (FIGS. Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8- 87, 40,9452.73 9452.24G and 5) Bip-[CAG]? 76Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-PKKKRKV-miniPEG2- 18, 40, 33 K(cyclo[FGFGRGRQ])-PEGi2-Nal-BRBRB- 10371.89 10371.336, 76 [CAG]7Ac-PKKK RK V-m iniPEG2- 18, 40, 34 K(cyclo[FGFGRGRQ])-PEGs-R-Bta-B- 9903.36 9902.776 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 35 K(cyclo[FGFGRGRQ])-PEGi2-BRB-Bip- 9974.42 9973.729, 76 [CAG]7Ac-PKKKRKV-miniPEG2- 18, 40, 36 K(cyclo[FGFGRGRQ])-PEGi2-BR-Bip-RB- 10327.01 10326.285, 76 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 37 9651.03 9650.4 K(cyclo[FGFGRGRQ])-PEG8-RF-B-[CAG]776 Ac-RBRRBR-miniPEG2- 20, 40, 41 9726.06 9725.5 K(cyclo[FGFGRGRQ])-PEG8-K-Bip-[CAG]776 Ac-kkkrk-miniPEG2-K(cyclo[FGFGRGRQ])- 12, 40, 42 9580.1 9579.4 PEG8-RF-[CAG]776 Ac-KKKRK-mini PEG2- 13, 40, 43 9630.16 9629.4 K(cyclo[FGFGRGRQ])-PEG8-R-NaI-[CAG]776 Ac-KKKRK-miniPEGz- 13, 40, 44 9580.1 9579.3 K(cyclo[FGFGRGRQ])-PEG8-rf-[CAG]776 Ac-RBKKBR-K(cyclo[FGFGRGRQ])-PEG8- 88, 40, 45 9552.89 9552.2R-Bip-[CAG]7 76 Ac-KKKRK-miniPEG2- 13, 40, 46 K(cyclo[FGFGRGRQ])-miniPEG2-FK- 9273.6 9273.176 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 47 9636.04 9635.3 K(cyclo[FGFGRGRQ])-PEG8-R-Bta-[CAG]776 Ac-K(me)-K(me)-K(me)-R(me)-K(me)- 14, 40, 48 miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF- 9650.24 9649.476 [CAG]vAc-PKKKRKV-miniPEG2- 18, 40, 49 K(cyclo[FGFGRGRQ])-mimPEG2-Val-Cit- 9450.8 9450.276 [CAG]7Ac-YArVRRrGPR-miniPEG2- 21, 40, 50 10179.72 10178.8 K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]7 76 Ac-KKKRK-mini PEG2- 13, 40, 51 K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PEG2- 9815.23 9814.576[CAG]7Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-KKKRK-miniPEG2- 13, 40, 52 K(cy cl o[FGFGRGRQ])-mini PEG2-R-Bta- 9502.85 9502.276 miniPEG2-[CAG]7Ac-RBRRBR-K(cyclo[FGFGRGRQ])- 87, 40, 53 9473.75 9473.1 miniPEG2-KF-PEG4-[CAG]7 76 Ac-PKKKRKV-miniPEG2- 54 (FIGS. 18, 40,K(cyclo[FGFGRGRQ])-miniPEG2-RFR- 9901.33 9902.5 4H and 5) 76 PEG4-[CAG]7Ac-KKKRK-miniPEG2- 55 (FIGS. 13, 40,K(cy cl o[FGFGRGRQ])-mini PEG2-RF-PEG4- 9548.9 9548.3 41 and 5) 76[CAG]7Ac-KKKRK-miniPEG2- 56 (FIGS. 13, 40,K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4- 9827.24 9826.6 4 J and 5) 76[CAG]7Ac-PKKKRK V-miniPEG2- 57 (FIGS. 13, 39,K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4- 10113.61 10113.8 4K and 5) 76[CAG]7Ac-KKKRK-miniPEG2- 13, 42, 58 K([cyclo[FGFRHRHQ])-miniPEG2-RF-PEG4- 10303.78 1030476 K([C1ick]-PEG4-[CAG]7)-NH2Ac-KKKRK-mini PEG2- 13, 41, 61 K(cyclo[FGFLRLRQ])-miniPEG2-RF-PEG4- 9661.11 9660.676 [CAG]7Ac-KKKRK-miniPEG2- 13, 43, 62 K(cyclo[FGFVRVRQ])-miniPEG2-RF-PEG4- 9661.27 9660.576 [CAG]7Ac-KKRK-miniPEG2- 63 K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9448.93 9448.3 1, 40, 76 [CAG]7Ac-KKRK-miniPEGs- 64 K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4- 9713.25 9712.5 1, 40, 76 [CAG]7Ac-KKKRK-miniPEG2- 65 (FIGS. 13, 40,K(cyclo[FGFGRGRQ])-PEG4-R-Bta- 9604.99 9604.3 4L and 5) 76 miniPEG2-[CAG]7Ac-YArVRRrGPR-miniPEG2- 21, 39, 66 K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4- 10238.79 10237.976 [CAG]767Ac-KKKRK-miniPEG2- 13, 40, (FIGS. 4M 9772.17 9771.5K(cyclo[FGFGRGRQ])-miniPEG2-rf-PEG4- 76 and 5)Bip-[CAG]7Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: 71 Ac-PKKKRKV-miniPEG2- 18, 40, (FIGS. 4N K(cycl o[FGFGRGRQ])-mini PEG2-RF-PEG4- 9892.32 9891.6 76 and 5) F-[CAG]7Ac-RB RRBR-miniPEG2- 20, 40, 72 K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9850.18 9849.576 Bta-[CAG]7Ac-KKKRK-miniPEG2- 73 (FIGS. 13, 40,K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9746.13 9747.4 40 and 5) 76 Nal-[CAG]7Ac-KKKRK-miniPEG2- 74 (FIGS. 13, 40,K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-Nal- 10024.47 10024.6 4P and 5) 76 [CAG]7Ac-PKKKRKV-miniPEG2- 75 (FIGS. 18, 39,K(cyclo[FfFGRGRQ])-miniPEG2-RF- 9930.37 9930.6 4Q and 5) 76 miniPEG2-Nal-[CAG]776 Ac-KKKRK-miniPEG2- 13, 40, (FIGS. K(cycl o[FGFGRGRQ])-mini PEG2-KF-PEG4- 9744.16 9743.576 GG and 5) Bip-[CAG]777Ac-PKKKRKV-miniPEG2- 18, 39, (FIGS. 4R 9690.11 9691.3K(cyclo[FfF’GRGRQ])-RF-PEG4-[CAG]7 76 and 5)Ac-KKKRK-miniPEG2- 13, 40, 79 9403.74 9403.3 K(cyclo[FGFGRGRQ])-RF-PEG4-[CAG]7 76 Ac-KKRK-miniPEG2- 80 K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9420.73 9420.3 1, 40, 76 [CAG]7Ac-KKKRK-mini PEG2- 13, 40, 81 K(cy cl o[FGFGRGRQ])-mini PEG2-R-(4-Py r)- 9549.89 9549.476 PEG4-[CAG]782 Ac-KKKRK-miniPEG2- 13, 40, (FIGS. 4S K(cyclo[FGFGRGRQ])-miniPEG2-RFRF- 9852.26 9851.733, 76 and 5) PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 83 K(cyclo[FGFGRGRQ])-PEG4-RF-miniPEG2- 9547.91 9548.476 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 84 K(cyclo[FGFGRGRQ])-miniPEG2-R-Bta- 9604.99 9604.576 PEG4-[CAG]7Ac-KKKRK-miniPEG2-K(cyclo[Phe(4-CN)- 13, 59, 85 G-Phe(4-CN)-GRGRQ])-miniPEG2-RF-PEG4- 9598.92 9598.476 [CAG]786 Ac-KKKRKR-miniPEG2- 17, 40, (FIGS. 4Z K(cyclo[FGFGRGRQ])-miniPEG2-F-PEG4- 9547.91 9548.476and 5) [CAG]7Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS:Ac-KKKRK-miniPEG2- 13, 40, 87 K(cyclo[FGFGRGRQ]-miniPEG2-RFlph- 9561.9476 PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 88 K(cyclo[FGFGRGRQ])-miniPEG2-RFE- 9428.75 9429.476 [CAG]789 Ac-KKKRK-miniPEG2- 13, 40, (FIGS. 4T K(cyclo[FGFGRGRQ])-miniPEG2-RFR- 9704.1 9704.676 and 5) PEG4-[CAG]7Ac-KKGRK-miniPEG2- 90 K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9477.78 9477.3 4, 40, 76 [CAG]7Ac-KKKRK-mini PEG2-K(cy cl o[G-f( N -me)- 13, 55, 91 9562.93 9562.4 FGrGrQ])-miniPEG2-RF-PEG4-[CAG]7 76 92 Ac-KKKRKF-miniPEGs- 16, 40, (FIGS. K(cyclo[FGFGRGRQ])-miniPEG2-R-PEG4- 9548.9 9548.476 DD and 5) [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 93 K(cyclo[FGFGRGRQ])-miniPEG2-RL-PEG4- 9514.88 9514.476 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 94 K(cyclo[FGFGRGRQ])-miniPEG2-RGF- 9605.95 9605.576 PEG4-[CAG]7Ac-KKKRK-mini PEG2- 95 (FIGS. 13, 40,K(cyclo[FGFGRGRQ])-miniPEG2-R-Tyr(Ph)- 9641 9640.4 4U and 5) 76 PEG4-[CAG]796 Ac-KKKRK-mini PEG13, 40, (FIGS. K(cy cl o[FGFGRGRQ])-mini PEG2-FR-PEG4- 9548.9 9548.376 EE and 5) [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 97 K(cyclo[FGFGRGRQ])-PEG4-R-Bip-PEG4- 9727.13 9726.676 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 98 K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 10019.46 10019.076 Bip-PEG4-[CAG]7Ac-KKKRK-miniPEG2-K(cyclo[(4-Pyr)-G-(4- 13, 46, 99 9550.88 9550.4Pyr)-GRGRQ] )-mi ni PEG2-RF-PEG4-[C AG ]776 100 Ac-KKKRK-mini PEG2- 13, 40, (FIGS. K(cyclo[FGFGRGRQ])-PEGs-R-Nal-PEG4- 9877.3 9876.876 BB and 5) [CAG]7Ac-KKKRK-miniPEG2- 101 (FIGS. 13, 57,K(cy cl o[GFRGFRGQ])-mini PEG2-RF-PEG4- 9548.9 9548.4 AA and 5) 76[CAG]7Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-KKKRK-miniPEG2- 13, 40, 102 K(cycl o[FGFGRGRQ])-mini PEG2-R-Phg- 9533.89 9534.476 PEG4-[CAG]7Ac-KKKRK-miniPEG2- 40, 32, 103 K(cyclo[FGFGRGRQ])-miniPEG2-KFKF- 9795.24 9795.776 PEG4-[CAG]7104 Ac-KKKRK-miniPEG2- (FIGS. 4W K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4- 9519.9 9520.5 40, 76 and 5) [CAG]7105 Ac-KKKRK-miniPEG2- 13, 40, (FIGS. 4X K(cyclo[FGFGRGRQ])-miiiiPEG2-RF- 9445.78 9446.376 and 5) mi ni PEG? - [C AG] 7106 Ac-KKKRK-mini PEG2- 13, 40, (FIGS. 4Y K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4- 9650.04 9650.476 and 5) [CAG]7Ac-KKKRK-miniPEG2- 13, 62, 107 K(cycl o[F AF ARGRQ])-mini PEG2-RF-PEG4- 9575.96 9576.476 [CAG]7Ac-KGKRK-miniPEG2- 108 K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4- 9477.78 9477.2 3, 40, 76 [CAG]7Ac-KKKRK-miniPEG2- 13, 40, 109 K(cyclo[FGFGRGRQ])-miniPEG2-R-Bip- 9625 9624.576 PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 110 K(cyclo[FGFGRGRQ])-miniPEG2-R-Nal- 9598.96 9598.576 PEG4-[CAG]7Ac-KKKRK-mini PEG2- 13, 40, 111 K(cyclo[FGFGRGRQ])-miniPEG2-R- 9694.06 9693.476 miniPEG2-F-PEG4-fCAG]7Ac-KKKRK-mini PEG2- 13, 40, 112 K(cyclo[FGFGRGRQ])-miniPEG2-R-Phe(3- 9573.91 9573.476 CN)-PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 113 K(cy cl o[FGFGRGRQ])-mini PEG2-HoArg- 9639.02 9638.576 Bip-PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 114 K(cyclo[FGFGRGRQ])-PEG4-rf-PEG4- 9651.03 9650.576 [CAG]7115Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])- 13, 40, (FIGS. 4FF 9651.03 96505miniPEG2-RF-PEG4-[CAG]7 76and 5)Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-KKRK-miniPEG2- 116 K(cycl o[FGFGRGRQ])-mini PEG2-RF-K- 9548.9 9548.4 1, 40, 76 PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 117 K(cyclo[FGFGRGRQ])-miniPEG2-RY-PEG4- 9564.9 9564.476 [CAG]7Ac-KKKRK-miniPEG2-K(cyclo[FGFG-Agp- 13, 63, 118 9492.79 9492.4G-Agp-Q])-miniPEG2-RF-PEG4-[CAG]7 76 Ac-KKKRK-miniPECn- 13, 40, 119 K(cyclo[FGFGRGRQ])-miniPEG2-FGR- 9605.95 9605.476 PEG4-[CAG]7120 Ac-KKKRK-miniPEG:- 13, 40, (FIGS. K(cyclo[FGFGRGRQ])-miniPEG2-RPF- 9646.01 9645.576 4CC and 5) PEG4-[CAG]7Ac-KKKRK-miniPEG2- 13, 40, 121 K(cyclo[FGFGRGRQ])-miniPEG2-Agp-Bip- 9596.94 9596.476 PEG4-[CAG]7Ac-KKRKK-miniPEG2- 122 K([cyclo[FGAGRGRQ])-mmiPEG2-RF-PEG4- 9471.82 94724 7, 50, 76 [CAG]7123 Ac-KKKRK-miniPEG2- 13, 40, (FIGS. 4V K(cyclo[FGFGRGRQ])-miniPEG2-Agp-F- 9519.86 9520.476 and 5) PEG4-[CAG]7Ac-K(cyclo[FGFGRGRQ])-miniPEG2- 40, 18, 124 10022.5 10023.1PKKKRKV-PEGs-RF-PEG4- [C AG17 76Table 1 OB.Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta- 38 9902.4 9901.8 18, 38, 76 GRGRQ])-PEG8-RF-[CAG]7Ac-KKKRK-PEG2-K(cyclo[GtFGrGrQ])- 39 9592.01 9593.4 13, 44, 76 PEG8-RF-[CAG]7Ac-kkkRK-PEG2-K(cyclo[GfFGrGrQ])- 40 9593.98 9593.3 11, 44, 76 PEGs-RF-[CAG]759(FIGS. Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])- 9596.11 9595.3 2, 40, 76 4LL and PEG2-RF-PEG4-[CAG]75)Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])- 60 9577.1 9576.4 13, 84, 76PEG2-RF-PEG44CAGI7Molecular Observed SEQ ID No. EEV-PMO conjugateweight mass NOS: (FIGS.4KK and5)Ac-KKKRK-PEG2-K(cyclo[FGFVRVRQ])- 62 9661 27 9660.5 13, 43, 76 PECh-RF-PEG4-[CAG]763(FIGS. Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])- 9448.93 9448.3 1, 40, 76 4 II and PEG2-RF-PEG4-[CAG]75)64(FIGS. Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])- 9713.25 9712.5 1, 40, 76 41III and PEG8-RF-PEG4-[CAG]75)68(FIGS. Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])- 9724.13 9723.6 13, 40, 76 4MM PEG2-RF-PEG4-F-[CAG]7and 5)Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ])- 69 9922.4 9921.7 13, 81, 76 PEG2-RF-PEG4-F-[CAG]7Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])- 2, 40, 76 70 9743.28 9742.5PEG2-RF -PEG4-F-[C AG]778(FIGS.9577.1 9576.3 13, 40, 76 4JJ and AC-KKKRK-PEG2-K(CVC1O[FGFGRGRQ])-_ 5) _ PEG2-RF-PEG4-[CAG]7Example 2: Evaluation of Compounds 1-20, 23-25, 27-29, 31-33, 35, 36, 39, 41-48, 50-58, 60, 65, 67, 71-75, 77, 79, 82, 84-86, 88, 89, 95, 99, 101, 103, 104, 107, 120, and 122-124 (Example 1) in a DM1 mouse model using the mouse DM1 Splicing Index (mDSI) assay

[0351] Compounds 1-20, 23-25, 27-29, 31-33, 35, 36, 39, 41-48, 50-58, 60, 65, 67, 71-75, 77, 79, 82, 84-86, 88, 89, 95, 99, 101, 103, 104, 107, 120, and 122-124 ofExample 1 (Table 10) were evaluated for their ability to correct the splicing of various transcripts aberrantly spliced in the DM1 disease state.Methods:

[0352] HSAlRmice (N = 10 per group, 5 males and 5 females, between 6 - 8 weeks of age at start of study) were administered a single intravenous (IV) bolus dose of test compounds (compounds 1-20, 23-25, 27-29, 31-33, 35, 36, 39, 41-48, 50-58, 60, 65, 67, 71-75, 77, 79, 82, 84-86, 88, 89, 95, 99, 101, 103, 104, 107, 120, and 122-124) at either 10 or 20mg / kg via the tailvein on Day 1 Additional groups of HSARmice and WT mice (N = 10) were administered a single dose of saline as negative and positive controls, respectively. Animals were sacrificed at either day 8 post dose administration (1 week readout) via CO2 asphyxiation followed by thoracotomy and exsanguination.

[0353] After the mice were euthanized, tibialis anterior (TA) muscle tissues were collected and homogenized by Omni Bead Mill Homogenizer, and RNA was extracted by Qiacube.

[0354] 500 ng - I pg RNA was reverse transcribed into cDNA using the High-Capacity cDNA Reverse Transcription Kit (ThermoFisher, Cat. No. 4368813) or Cells-to-CT Bulk Fast Advance RT Reagents (ThermoFisher, Cat. No. A39110) according to the manufacturer’s protocol. 10 L qPCR reactions were prepared with 2 pL input cDNA using the TaqMan Fast Advanced Master Mix for qPCR kit (ThermoFisher, Cat. No. 4444965) and TaqMan probes for Atp2al, Bini, Clasp, Clcnl, Kifl3a, Mbnl 1, Vps39, Nfix, or Ryrl. TaqMan FAM probes were designed based on mis-spliced events previously reported by Tanner et al. (NAR 2021, doi.org / 10.1093 / nar / gkab022) and VIC probes were designed to measure expression of constitutive exons within the same transcript. qPCR was performed on an Applied Biosystems QuantStudio 12k Flex using the fast ramp setting. TaqMan probe information can be found in Table 11.Table 11.Mbnll FAM Probe ThermoFisher Scientific mm01291481 mlMbnll VIC Probe ThermoFisher Scientific mm00490954 mlClcnl FAM Probe ThermoFisher Scientific mmOl 162626__glClcnl VIC Probe ThermoFisher Scientific mmOO 658624 ni 1Atp2al FAM Probe ThermoFisher Scientific mmO 1275328 glAtp2al VIC Probe ThermoFisher Scientific mm01275317 mlRyrl FAM Probe IDT RYR1 misplaced Set3Ryrl VIC Probe IDT Mm. PT.56a.10456426Ki fl 3a FAM Probe IDT mmu-Kifl3a-altexon Set3Kifl3a VIC Probe IDT Mm. PT.58.30478040Vps39 FAM: Probe IDT vps39-FAM-ait Set 1Vps39 VIC Probe IDT Mm. PT.58.5348801Nfix FAM Probe IDT nfix-FAM-alt Set 4Nfix VIC Probe IDT Mm, PT.58.8017145Clasp In FAM Probe IDT Clasp 1-FAM-alt Set 1Clasp Ex FAM Probe IDT Clasp 1-2-FAM-alt Set 1Clasp In VIC Probe IDT Mm. PT.58.6876394Clasp Ex VIC Probe IDT Mm. PT.58.12669013Bini FAM Probe IDT 400271073 mmu-Binl -Hook-Set 2Bini VIC Probe IDT Mm. Pt.58.32840399

[0355] The ACt method was used to calculate the relative quantification (RQ) between FAM and VIC probes for each target per sample. For each sample / , normalized splicing values were calculated for each splice event as l-[(RQ / ,f- - RQM?) / ( QHSALRJ - RQwiWow)], where QwildtypeJ and RQJ7S4ZT?,;are the mean relative quantification for transcript j within wild type and vehicle treated mice, respectively. The overall mouse DM1 Splicing Index (mDSI) was then calculated as the mean of all the normalized splicing values per sample. In this normalization, the saline-treated HSA[ Rmice average is set to 1.0, and saline-treated WT mice average set to 0.0.

[0356] Compounds 14, 16, 19, 20, 23-25, 27-29, 31-33, 39, 41, 47, 48, 50-52, 54-58, 65, 67, 71- 75, 77, 79, 82, 84-86, 88, 89, 95, 101, 103, 104, 107, 120, 122, and 123 were shown to have mDSI data of 0-0.7 at either 10 or 20 mg / kg.

Claims

1. CLAIMS2.What is claimed is.

1. A compound of Formula III:

5.

6. or a pharmaceutically acceptable salt thereof;7.a8.R20is H or9. 11.al, a2, a3, and a4 are each independently 0 or 1, wherein at least one of a2, a3, and a4 is 1;12.wl, w2, and w3 are each independently 0 or 1, wherein at least one of w2 and w3 is 113.AA1 is an amino acid residue or a peptide comprising 2 to 10 amino acid residues;14.AAA2, AA3, and AA4 are each independently an amino acid residue or a peptide comprising 1 to 6 amino acids residues, wherein at least one of AA2, AA3, and AA4 is present in the compound and comprises a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;15.j1, j1, and j2 are each independently an integer from 1 to 4;16.xl, x2, and x3 are each independently an integer from 1 to 14;17.n is an integer from 0 to 3; y is an integer from I to 5;18.ml is 0 or 1;19.o20.■ <k 121.M comprises -NH-,22.

23. ’, or a heteroaryl wherein t is an integer from 0 to 10;24.R1, R2, R3, R4, R5, R6, and R7are each independently the side chain an amino acid residue, and25.cargo comprises an oligonucleotide comprising the sequence:26.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG-3 ' (SEQ ID NO: 74),27.5'-CAG CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 73), 5 -CAG CAG CAG CAG CAG CAG CAG CAG -3 (SEQ ID NO: 72),28.5 -CAG CAG CAG CAG CAG CAG CAG -3 '(SEQ ID NO: 71), 5' -CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 70),29.5' -CAG CAG CAG CAG CAG -3' (SEQ ID NO: 69),30.5 -CAG CAG CAG CAG -3'(SEQ ID NO: 68),31.5'-CAG CAG CAG -3, or32.5 -CAGCAG-3'2. The compound of claim 1, wherein:34.R5and R ' are the side chain of arginine;35.R4and R° are H or an amino acid side chain; and36.two of R1, R2, and R3, are, independently the side chain of phenylalanine and one of R1, R2, and RJis H, or37.or R1, R2, and R3are the side chain of phenylalanine,3. The compound of claim 1 or 2, wherein the each of AA2, AA3, and AA4 present in the compound is independently selected from Bip, F, R, Bta, Nal, RF, RK, FK, K-Bip, R- Bip, R-Bta, R-Nal, V-Cit, Agp-Bip, Agp-F, Cit-F, EF, FR, R-(2-Pyr), R-(3-Pyr), R-(4- Pyr), R-(Phe(l)), RG, RL,(Rme)-(F(N-me)), R-(Phe(3-CN)), R-(Trp(5-F)), R-(Tyr(Ph)), RW, RY, SF, R-Bta-B, KKKRK (SEQ ID NO: 13). KRKR (SEQ ID NO: 28), RF-B, RFR,RPF, RK-Nal, rk-Nal, FGR, (HoArg)-Bip, R-Bip-R, RFK, RGF, R-Nal-R, BRB-Bip (SEQ ID NO: 29), KRK-Nal (SEQ ID NO: 30), kkkr-Na 3 (SEQ ID NO: 31), KFKF (SEQ ID NO: 32), RFRF (SEQ ID NO: 33), KKRK-Nal (SEQ ID NO: 34), Bip-BRBRB (SEQ ID NO: 35), Nal-BRBRB (SEQ ID NO: 36), KKKRK-Nal (SEQ ID NO: 37), RFE, R-(Phg), R- (Hph), (Pcpa)-F, BR-Bip-RB (SEQ ID NO: 85), RRFF (SEQ ID NO: 86), and FRF.

4. The compound of any one of claims 1 to 3, wherein al is 1 and AA1 is selected from K, KK, RK, KFK, KRK, KKK, KKRK (SEQ ID NO: 1), KKFRK (SEQ ID NO: 2), KGKRK (SEQ ID NO: 3), KKGRK (SEQ ID NO: 4), KKKGK (SEQ ID NO: 5), KKRKG (SEQ ID NO: 6), KKRKK (SEQ ID NO: 7), KKTRK (SEQ ID NO: 8), TKKRK (SEQ ID NO: 9), pkkkrkv (SEQ ID NO: 10), kkkRK (SEQ ID NO: 1 I), kkkrk (SEQ ID NO: 12), KKKRK (SEQ ID NO: 13), K(me)-K(me)-K(me> R(me)-K(me) (SEQ ID NO: 14), TKKRK (SEQ ID NO: 15), KKKRKF (SEQ ID NO: 16), KKKRKR (SEQ ID NO: 17), PKKKRKV (SEQ ID NO: 18), RBKKRB (SEQ ID NO: 19), RBRRBR (SEQ ID NO: 20), YArVRRrGPR (SEQ ID NO: 21), RFGRK (SEQ ID NO: 22), KKKHH (SEQ ID NO: 15), KBKBKBRBK (SEQ ID NO: 23), RFKKRFK (SEQ ID NO: 24), RBKKBR (SEQ ID NO: 80), N(Lys)-N(Lys)-N(Lys)-N(Arg)- N(Lys) (SEQ ID NO: 25), N(Arg)-B-N(Arg)-N(Arg)-B-N(Arg) (SEQ ID NO: 26), and N(Lys)-N(Lys)-N(L.ys)-N(Arg)-N(Lys) (SEQ ID NO: 27).

5. The compound of claim 1, wherein the compound is of Formula A:H R29-(AA1>"“H (M | cargo ’mt42. 44.or a pharmaceutically acceptable salt thereof;45.wherein:46.O J47.R20isH or '' b48.wl is 0 or 1;49.al is 0 or 1;50.a3 is 1;51.AA1 is an amino acid residue or a peptide comprising 2 to 10 amino acid residues;52.AA3 is an amino acid residue or a peptide comprising 1 to 6 amino acids residues comprising a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;53.j 1 and j2 are each independently an integer from 1 to 4;54.xl and x2 are each independently an integer from 1 to 14;55.n is an integer from 0 to 3,56.y is an integer from 1 to 5;57.ml is 0 or 1; M' comprises -NH-,58.

59. or a heteroaryl wherein t is an integer from 0 to 10;60.Rl, R2, R3, R4, R3, R6, and R7are each independently the side chain an amino acid residue; and61.cargo comprises an oligonucleotide comprising the sequence:62.5 -CAG CAG C G CAG CAG CAG C G CAG CAG CAG-3 '(SEQ ID NO:63.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG -3 '(SEQ ID NO: 73), 5 -CAG CAG CAG CAG CAG CAG CAG CAG -3 (SEQ ID NO: 72),64.5' -CAG CAG CAG CAG CAG CAG CAG -3 "(SEQ ID NO: 71), 5 '-CAG CAG CAG CAG CAG CAG -3 '(SEQ ID NO: 70),65.5 -CAG CAG CAG CAG CAG -3 ' (SEQ ID NO: 69),66.5 -CAG CAG CAG CAG -3' (SEQ ID NO: 68),67.5' -CAG CAG CAG -3, or68.5'-CAG CAG -3'.

6. The compound of claim 5, wherein:70.R’ and R7are the side chain of arginine;71.R4and R6are H or an amino acid side chain; and72.two of R1, R2, and R3, are, independently the side chain of phenylalanine and one of R1, R2, and R3is H, or73.or R1, R2, and R3are the side chain of phen lalanine.

7. The compound of claim 5 wherein, AA3 comprises phenylalanine and arginine; or naphthylalanine or biphenylalanine.75.O8. The compound of claim 5, wherein R20is77.

78. C and AA1 comprises KKKRK (SEQ ID NO: 13); YArVRRrGPR (SEQ ID NO: 21 ); PKKKRKV (SEQ ID NO: 18); RBRRBR (SEQ ID NO: 20); or K(me)-K(me)-K(me)-R(me)-K(me) (SEQ ID NO: 14). The compound of claim 5, wherein the cargo is a PMO and the compound is selected from:79.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-[CAG]7(SEQ ID NOS: 18, 40, 76);80.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-Bip-[CAG]7 (SEQ ID NOS: 18, 40, 76);81.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFRRRRQ])-PEG12-(2-Nal)-[CAG]7(SEQ ID NOS: 18, 81, 76);82.Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-RK-(2-Nal)-[CAG]7(SEQ ID NOS: 40, 76);83.Ac-KK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-KRK-(2-Nal)-[CAG]7(SEQ ID NOS: 40, 30, 76);84.Ac-K-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-KKRK-(2-Nal)-[CAG]7 (SEQ ID NOS: 40, 34, 76);85.Ac-K(cyclo[FGFGRGRQ])-PEG12-KKKRK-(2-Nal)-[CAG]7(SEQ ID NOS: 40, 37, 76); Ac-KKK-K(cyclo[FGFGRGRQ])-PEG12-RK-(2-Nal)-[CAG]7(SEQ ID NOS: 89, 40, 76); Ac-KKK-K(cyclo[FGFGRGRQ])-PEG12-rk-(2-nal)-[CAG]7(SEQ ID NOS: 89, 40, 76); Ac-K(cyclo[FGFGRGRQ])-PEG12-kkkr-(2-nal)-[CAG]7(SEQ ID NOS: 40, 31, 76); Ac-pkkkrkv-miniPEG2-kcyclo[fGfrrrrQ]-PEG12-dNal-[CAG]7(SEQ ID NOS: 10, 45, 76);86.Ac-pkkkrkv-miniPEG2-kcyclo[fGfrrrrQ]-PEG12-Nal-[CAG]7(SEQ ID NOS: 10, 45, 76); Ac-pkkkrkv-miniPEG2-k(cyclo[FGFRRRRQ])-PEG12-dNal-[CAG]7(SEQ ID NOS: 10, 81, 76);87.Ac-pkkkrkv-miniPEG2-k(cyclo[fGfGrGrQ])-PEG12-dNal-[CAG]7(SEQ ID NOS: 10, 83, 76);88.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-Bip-BRBRB-[CAG]7(SEQ ID NOS: 18, 40, 35, 76);89.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-[CAG]7 (FIG. 4D) (SEQ ID NOS: 13, 40, 76);90.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]7(FIG. 4E) (SEQ ID NOS: 13, 40, 76); Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8-Bip-[CAG]7 (SEQ ID NOS:87, 40, 76); Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-Nal-BRBRB-[CAG]7(SEQ ID NOS: 18, 40, 36, 76);91.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-B-[CAG]7(SEQ ID NOS: 18, 40, 76);92.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-BRB-Bip-[CAG]7(SEQ ID NOS: 13, 40, 29, 76);93.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEG12-BR-Bip-RB-[CAG]7(SEQ ID NOS:18, 40, 85, 76);94.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-B-[CAG]7 7(SEQ ID NOS: 13, 40, 76);95.Ac-PKKKRKV-PEG2-k(cyclo[Bta-G-Bta-GRGRQ])-PEG8-RF-[CAG]7 (SEQ ID NOS: 18, 38, 76),96.Ac-KKKRK-miniPEG2-K(cyclo[GffGrGrQ])-PEG8-RF-[CAG]7(SEQ ID NOS: 13, 44, 76);97.Ac-kkkRK-miniPEG2-K(cyclo[GfFGrGrQ])-PEG8-RF-[CAG]7(SEQ ID NOS: 87, 44, 76);98.Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-K-Bip-[CAG]7 (SEQ ID NOS:87, 40, 76);99.Ac-kkkrk-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]7(SEQ ID NOS: 11, 40, 76);100.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-[CAG]7 (SEQ ID NOS: 13, 40, 76);101.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-rf-[CAG]7(SEQ ID NOS: 13, 40, 76);102.Ac-RBKKBR-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-[CAG]7(SEQ ID NOS: 88, 40, 76); Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FK-[CAG]7 (SEQ ID NOS: 13, 40, 76);103.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bta-[CAG]7 (SEQ ID NOS: 13, 40, 76);104.Ac-K(me)-K(me)-K(me)-R(me)-K(me)-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]7 (SEQ ID NOS: 14, 40, 76); Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Val-Cit-[CAG]7(SEQ ID NOS: 18, 40, 76);105.Ac-YArVRRrGPR-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]7(SEQ ID NOS: 21, 40, 76); or106.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFE-[CAG]7(SEQ ID NOS: 13, 40, 76),107.wherein:108.miniPEG2 is -(CH2-CH2-O)2-CH2-CO-;109.PEG2 is -(CH2-CH2-O)2-CH2- CH2-CO-;110.PEG8 is -(CH2-CH2-O)8-CH2-CH2-CO-;111.PEG12 is -(CH2-CH2-O)12-CH2-CH2-CO-; and112.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

10. The compound of claim 5, wherein cargo is a PMO and the compound is selected from:114.Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-[CAG]7 (SEQ ID NOS: 13, 40, 76);115.Ac-RBRRBR-K(cyclo[FGFGRGRQ])-PEG8-Bip-[CAG]7(FIG. 4G) (SEQ ID NOS:87, 40, 76);116.Ac-KKKRK-PEG2-K(cyclo[GfFGrGrQ])-PEG8-RF-[CAG]7(SEQ ID NOS: 13, 44, 76); Ac-kkkRK-PEG2-K(cyclo[GfFGrGrQ])-PEGs-RF-[CAG]7(SEQ ID NOS:87, 44, 76); Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-[CAG]7(SEQ ID NOS: 13, 40, 76), Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-FK-[CAG]7(SEQ ID NOS: 13, 40, 76); and117.Ac-pkkkrkv-PEG2-k(cyclo[fGfrrrrQ])-PEGi2-Nal-[CAG]7(SEQ ID NOS: 10, 45, 76), wherein:118.PEG2 is (CH2-CH2-O)2-CH2- CH2-CO-;119.PEGs is -(CH2-CH2-O)8-CH2-CH2-CO-;120.PEG12 is -(CH2-CH2-O)12-CH2-CH2-CO-; and121.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

11. The compound of claim 1, wherein the compound is of Formula B:i I 0 0 I l JI J k z Z F* V / M (AA3; v P J d h bH 12*3' *3 6 § > 4‘ NH Q-Z k f a c Z-4' HN. < <> Y*HR?' O^VNH |LzA2«5 X / tKZ o123.

124. 0 ^4125.or a pharmaceutically acceptable salt thereof;126.wherein:127.R128. 129.20isH or130.wl is 0 or 1;131.al is 0 or 1;132.a3 is 1;133.A Al is an amino acid residue or a peptide comprising 2 to 10 amino acid residues;134.AA3 is an amino acid residue or a peptide comprising 1 to 6 amino acids residues comprising a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;135.j 1, j2, and j3 are each independently an integer from 1 to 4;136.xl, x2, and x3 are each independently an integer from 1 to 14,137.n is an integer from 0 to 3;138.y is an integer from 1 to 5;139.ml is 0 or 1; M' comprises -NH-,140.

141. or a heteroaryl wherein t is an integer from 0 to 10;142.Rl, R2, R3, R4, R3, R6, and R7are each independently the side chain an amino acid residue;143.R40is H; and144.cargo comprises an oligonucleotide comprising the sequence:145.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG-3 ' (SEQ ID NO:146.5'-CAG CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 73), 5 -CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 72),147.5 -CAG CAG CAG CAG CAG CAG CAG -3 ' (SEQ ID NO: 71), 5' -CAG CAG CAG CAG CAG CAG -3 '(SEQ ID NO: 70),148.5 -CAG CAG CAG CAG CAG -3' (SEQ ID NO: 69),149.5 -CAG CAG CAG CAG -3' (SEQ ID NO: 68),150.5 -CAG CAG CAG -3, or151.5 '-CAG CAG -3'.

12. The compound of claim 11, wherein:153.R' and R7are the side chain of arginine,154.R4and R6are H or an amino acid side chain; and155.two of R1, R2, and R3, are, independently the side chain of phenylalanine and one of R1, R2, and R3is H, or156.or Rl, R2, and R3are the side chain of phenylalanine.

13. The compound of claim 11, wherein AA3 comprises a charged amino acid residue and an aromatic amino acid residue.

14. The compound of claim 11, wherein AA3 comprises an arginine residue or a „. NH158.r159.MH161.

162. O, residue and an aromatic amino acid residue.

15. The compound of claim 11, wherein, AA3 comprises arginine and phenylamine, arginine and biphenylalanine; arginine and 3-(3-benzothienyl)-alanine; arginine and164.NH166.

167. , lysine and phenylamine or168.

169. and phenylamine.170.o16. The compound of claim 11, wherein R20is172.

173. ' V and AA1 comprises PKKKRKV (SEQ ID NO: 18), KKKRKR (SEQ ID NO: 17), or KKKRK (SEQ ID NO: 13).

17. The compound of claim 11, wherein the cargo is a PMO and the compound is selected from:175.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7(SEQ ID NOS: 18, 39, 76);176.Ac-KKKRK-niiniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PEG2-[CAG]7(SEQ ID NOS: 13, 40, 76);177.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Bta-miniPEG2-[CAG]7 (SEQ ID NOS: 13, 40, 76);178.Ac-RBRRBR-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-[CAG]7(SEQ lDNOS:87, 40;179.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFR-PEG4-[CAG]7(FIG.180.4H) (SEQ ID NOS: 18, 40, 76); Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7(FIG. 4I) (SEQ ID NOS: 13, 40, 76);181.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-[CAG]7 (FIG. 4 J) (SEQ ID NOS: 13, 40, 76);182.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-[CAG]7(FIG. 4K) (SEQ ID NOS: 18, 39, 76);183.Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])- PEG2-RF-PEG4-[CAG]7(SEQ ID NOS: 2, 40, 76);184.Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])-PEG2-RF-PEG4-[CAG]7 (FIG. 4KK) (SEQ ID NOS: 13,, 76);185.Ac-KKKRK-miniPEG2-K(cyclo[FGFLRLRQ])-miniPEG2-RF-PEG4-[CAG]7(SEQ ID NOS: 13, 41, 76);186.Ac-KKKRK-PEG2-K(cyclo[FGFWWQ])-PEG2-RF-PEG4-[CAG]7 (SEQ ID NOS: 13, 43, 76);187.Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])- PEG2-RF-PEG4-[CAG]7188.(FIG. II) (SEQ ID NOS: 1, 40, 76);189.Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-[CAG]7(FIG. 4HH) (SEQ ID NOS: I, 40, 76);190.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ)-PEG4-R-Bta-miniPEG2-[CAG]7(FIG.191.4L) SEQ ID NOS: 13,, 76); and192.Ac-YArVRRrGPR-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7 (SEQ ID NOS: 21, 39, 76),193.wherein:194.miniPEG2 is -(CH2-CH2-O)2-CH2-CO-;195.PEG2 is -(CH2-CH2-O)2-CH2-CH2-CO-;196.PEG4is -(CH2-CH2-O)4-CH2-CH2-CO-;197.PEG8 is -(CH2-CH2-O)8-CH2-CH2-CO-;198.PEG12 is -(CH2-CH2-O)i2-CH2-CH2-CO-; and199.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

18. The compound of claim 11, wherein the compound is selected from:Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-PMO (FIG. JJ) (SEQ ID NOS: 13, 40, 76);201.Ac-KKRK-miniPEG2-K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 1, 40, 76);202.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-(4-Pyr)-PEG4-PMO (SEQ ID NOS: 13, 40, 76);203.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFRF-PEG4-PMO (FIG. 4S) (SEQ ID NOS: 13, 40, 33, 76);204.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Bta-PEG4-PMO (SEQ ID NOS: 13, 40, 76);205.Ac-KKKRK-miniPEG2-K(Phe(4-CN)-G-Phe(4-CN)-GRGRQ)-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 13, 59, 76);206.Ac-KKKRKR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-F-PEG4-PMO (FIG. 4Z) (SEQ ID NOS: 17, 40, 76);207.Ac-KKKRKR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-F-PEG4-PMO (SEQ ID NOS: 17, 40, 76),208.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFR-PEG4-PMO (FIG. 4T) SEQ ID NOS: 13, 40, 76);209.Ac-KKGRK-miniPEG2-K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NO: 4, 40, 76);210.Ac-KKKRK-miniPEG -K(cyclo[G-(f(me))-FGrGrQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 13, 61, 76);211.Ac-KKKRKF-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-PEG4-PMO (FIG. 4DD) (SEQ ID NOS: 16, 40, 76);212.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RL-PEG4-PMO (SEQ ID NOS: 13, 40, 76);213.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RGF-PEG4-PMO(SEQ ID NOS: 13, 40, 76);214.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Tyr(Ph)-PEG4-PMO (FIG.215.4U) (SEQ ID NOS: 13, 40, 76), Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FR-PEG4-PMO (FIG. 4EE) (SEQ ID NOS: 13, 40, 76);216.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bip-PEG4-PMO (SEQ ID NOS: 13, 40, 76);217.Ac-KKKRK-miniPEG2-K(cyclo[(4-Pyr)-G-(4-Pyr)-GRGRQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 13, 46, 76);218.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PEG4-PMO (FIG. 4BB) (SEQ ID NOS: 13, 40, 76);219.Ac-KKKRK-miniPEG2-K(cyclo[GFRGFRGQ])-miniPEG2-RF-PEG4-PMO (FIG. 4AA) (SEQ ID NOS: 13, 76);220.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KFKF-PEG4-PMO (SEQ ID NOS: 13, 40, 32, 76);221.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-PMO (FIG. 4W) (SEQ ID NOS: 13, 40, 76);222.Ac-KKKRK-miniPEG2-K(cyclo[FAFARGRQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 13, 62, 76),223.Ac-KGKRK-miniPEG2-K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 3, 40, 76);224.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Bip-PEG4-PMO (SEQ ID NOS: 13, 40, 76);225.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Nal-PEG4-PMO (SEQ ID NOS: 13, 40, 76);226.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Phe(3-CN)-PEG4-PMO (SEQ ID NOS: 13, 40, 76);227.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-HoArg-Bip-PEG4-PMO (SEQ ID NOS: 13, 40, 76);228.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-rf-PEG4-PMO (SEQ ID NOS: 13, 40, 76);229.Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-PMO (FIG. 4FF) (SEQ ID NOS: 13, 04, 76); Ac-KKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-K-PEG4-PMO (SEQ ID NOS: 1, 40, 76);230.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RY-PEG4-PMO (SEQ ID NOS: 13, 40, 76);231.Ac-KKKRK-miniPEG2-K(cyclo[FGFG-Agp-G-Agp-Q])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 13, 63, 76);232.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FGR-PEG4-PMO (SEQ ID NOS: 13, 40, 76);233.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RPF-PEG4-PMO (FIG. 4CC) (SEQ ID NOS: 13, 40, 76);234.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Agp-Bip-PEG4-PMO (SEQ ID NOS: 13, 40, 76);235.Ac-KKRKK-miniPEG2-K(cyclo[FGAGRGRQ])-miniPEG2-RF-PEG4-PMO (SEQ ID NOS: 13, 50, 76); and236.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Agp-F-PEG4-PMO (FIG> 4V) (SEQ ID NOS: 13, 40, 76),237.wherein:238.miniPEG2is -(CH2-CH2-O)2-CH2-CO-;239.PEG? is -(CH2-CH2-O)2-CH2-CH2-CO-;240.PEG4 is -(CH2-CH2-O)4-CH2-CH2-CO-;241.PEG8 is -(CH2-CH2-O)8-CH2-CH2-CO-;242.PEG12 is -(CH2-CH2-O)12-CH2-CH2-CO-; and243.PMO is a PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

19. The compound of claim 12, wherein the cargo is a PMO and the compound is selected from:245.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFE-[CAG]7(SEQ ID NOS: 13, 40, 76);246.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-miniPEG2-[CAG]7(SEQ ID NOS: 13, 40, 76), Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Phg-PEG4-[CAG]7(SEQ ID NOS: 13, 40, 76);247.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-miniPEG2-[CAG]7(FIG.248.4Y) (SEQ ID NOS: 13, 40, 76); and249.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-[CAG]7(FIG. 4X) (SEQ ID NOS: 13, 40, 76),250.wherein:251.miniPEG2is -(CH2-CH2-O)2-CH2-CO-;252.PEG4is –(CH2-CH2-O)4-CH2-CH2-CO-; and253.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

20. The compound of claim 12, wherein the cargo is a PMO and the compound is selected fro:255.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7 (FIG.256.4A) (SEQ ID NOS: 18, 39, 76);257.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-[CAG]7(SEQ ID NOS: 13, 40, 76),258.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-Bta-miniPEG2-[CAG]7(SEQ ID NOS: 13, 40, 76);259.Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-[CAG]7 (FIG. 4LL) (SEQ ID NOS: 2, 40, 76);260.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-miniPEG2-[C AG]7(SEQ ID NOS: 13, 40, 76);261.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Bip-PEG2-[CAG]7(SEQ ID NOS: 13, 40, 76);262.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7(SEQ ID NOS: 13, 40, 76);263.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-[CAG]7(SEQ ID NOS: 13, 39, 76); and264.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-[CAG]7(SEQ ID NOS: 13, 40, 76), wherein:265.miniPEG2is -(CH2-CH2-O)2-CH2-CO-;266.PEG4is -(CH2-CH2-O)4-CH2-CH2-CO-;267.PEG8is -(CH2-CH2-O)8-CH2-CH2-CO-;268.PEG12is -(CH2-CH2-O)12-CH2-CH2-CO-; and269.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

21. The compound of claim 5, wherein cargo is a PMO and the compound is selected from:271.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-[CAG]7 (FIG. 41);272.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-PEG8-RF-PEG4-[CAG]7 (FIG. 4K);273.Ac-KKKRK-PEG2-K(cyclo[FGRGFGRQ])-PEG2-RF-PEG4-[CAG]7 (FIG. 4KK),274.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-R-Bta-miniPEG2-[CAG]7 (FIG. 4L);275.Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-[CAG]7 (FIG 4LL);276.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Agp-F-PEG4-[CAG]7 (FIG.277.4V);278.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-[CAG]7 (FlG. 4W);279.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-miniPEG2-[CAG]7 (FIG.280.4X);281.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG4-RF-PEG4-[CAG]7; and282.Ac-KKKRKR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-F-PEG4-[CAG]7 (FIG. 4Y),283.wherein:284.miniPEG2is -(CH2-CH2-O)2-CH2-CH2-CO-;285.PEG2is -(CH2-CH2-O)2-CH2-CH2-CO-; PEG8is -(CH2-CH2-O)8-CH2-CH2-CO-;286.PEG12 is “(CH2-CH2-O)I2-CH2-CH2-CO-; and287.[CAG is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.288.The compound of claim 5, wherein cargo is a PMO and the compound is selected from:289.Ac-KKKRK-miniPEG2-K(cyclo[GFRGFRGQ])-miniPEG2-RF-PEG4-[CAG]7 (FIG. 4AA);290.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-R-Nal-PEG4-[CAG]7 (FIG. 4BB);291.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RPF-PEG4-[CAG]7 (FIG.292.4CC);293.Ac-KKKRKF-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-R-PEG4-[CAG]7 (FIG. 4DD);294.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-FR-PEG4-[CAG]7 (FIG. 4EE);295.Ac-KKKRK-PEG4-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7 (FIG 4FF);296.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RFR-PEG4-[CAG]7 (FIG. 4H);297.Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-[CAG]7 (FIG. 4HH);298.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-[CAG]7 (FIG. 41);299.and300.Ac-KKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-[CAG]7 (FIG. 411),301.wherein:302.miniPEG2is -(CH2-CH2-O)2-CH2-CH2-CO-;303.PEG2is -(CH2-CH2-O)2-CH2-CH2-CO-;304.PEG8is -(CH2-CH2-O)8-CH2-CH2-CO-;305.PEG12is -(CH2-CH2-O)12-CH2-CH2-CO-; and [CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus,23. The compound of claim 1, wherein the compound is of Formula C:307.->>> H ■; S, H R l \308.• K A „ K <AM> T (» Wargo a-s Qi Ylf Y H \ 7M (AA3L v O / «* r A o A -i2o i J -Jw ^1¥; N. H GY309.< o Q L„4 R* RY H' *" V O,Y«H HNR!310.A'-v„311.«* >. < o312.

313. O314.or a pharmaceutically acceptable salt thereof;315.wherein:316.O317.R318. 319.20isH or ''320.wl is 0 or 1;321.al is 0 or 1;322.a3 is 1;323.a4 is 1;324.AA1 is an amino acid residue or a peptide comprising 2 to 10 amino acid residues;325.AA3 and AA4 are each independently an amino acid residue or a peptide comprising 1 to 6 amino acids residues, wherein AA3 comprises a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;326.j 1, j2, and j3 are each independently an integer from 1 to 4; xl, x2, and x3 are each independently an integer from 1 to 14;327.n is an integer from 0 to 3;328.y is an integer from 1 to 5;329.ml is 0 or 1;330.O331., JU332.M' comprises -NH-,333.

334. *■, or a heteroaryl wherein t is an integer from 0 to 10;335.Rl, R2, R3, R4, R5, R6, and R7are each independently the side chain an amino acid residue; and336.cargo comprises an oligonucleotide comprising the sequence:337.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG-3 ' (SEQ ID NO: 74),338.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG -3 ' (SEQ ID NO: 73), 5'-CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 72),339.5' -CAG CAG CAG CAG CAG CAG CAG -3 '(SEQ ID NO: 71), 5 -CAG CAG C G CAG CAG CAG -3'(SEQ ID NO: 70),340.5 -CAG CAG CAG CAG CAG -3 (SEQ ID NO: 69),341.5 -CAG CAG CAG CAG -3 ' (SEQ ID NO: 68),342.5' -CAG CAG CAG -3, or343.5 '-CAG CAG -3'.

24. The compound of claim 23 wherein:345.R3and R7are the side chain of arginine;346.R4and R6are H or an amino acid side chain; and347.two of R’, R2, and R3, are, independently the side chain of phenylalanine and one of R1, R2, and R3is H, or348.or R1, R2, and R3are the side chain of phenylalanine.

25. The compound of claim 23, wherein:350.AA3 and AA4 comprise an aromatic amino acid; or AA3 comprises a charged amino acid and an aromatic amino acid and AA4 comprises an aromatic amino acid.

26. The compound of claim 23, wherein the cargo is a PMO and the compound is selected fro:352.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-Agp-F-PEG4-[CAG]7(SEQ ID NOS: 13, 40, 76);353.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-miniPEG2-(2-Nal)- [CAG]7(SEQ ID NOS: 18, 40, 76);354.Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEGi2-(2-Nal)-miniPEG2-(2-Nal)-[CAG]7(SEQ ID NOS: 18, 39, 76);355.Ac-KKKRK-miniPEG2-K(cyclo[FfFGRGRQ])-PEGi2-Bip-miniPEG2-Bip-[CAG]7(SEQ ID NOS: 13, 39, 76);356.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-Bip-[CAG]7(FIG. 4B) (SEQ ID NOS: 18, 39, 76);357.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-miniPEG2-Bip-[CAG]7(SEQ ID NOS: 18, 39, 76);358.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-[CAG]7(SEQ ID NOS: 13, 40, 76);359.Ac-RBRRBR-K(cyclo[FfFGRGRQ])-PEGi2-Nal-miniPEG2-Nal-[CAG]7(SEQ ID NOS:87, 39, 76);360.Ac-RBRRBR-K(cyclo[FGFGRGRQ] PEG4-Nal-miniPEG2-Nal-[CAG]7(FIG. 4F) (SEQ ID NOS: 87, 76);361.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-rf-PEG4-Bip-[CAG]7(FIG.362.4M) (SEQ ID NOS: 13, 40, 76);363.Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])- PEG2-RF-PEG4-F-[CAG]7(FIG. 4MM) (SEQ ID NOS: 13, 40, 76);364.Ac-KKKRK-PEG2-K(cyclo[FGFRRRRQ])- PEG2-RF-PEG4-F-[CAG]7(SEQ ID NOS: 13, 81, 76);365.Ac-KKFRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-[CAG]7(SEQ ID NOS: 2, 40, 76); Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F-[CACT]7(FIG.366.4N) (SEQ ID NOS: 18, 40, 76);367.Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bta-[CAG]7(SEQ IDNOS:87, 40, 76);368.Ac-KKKRK-miniPEG2-K([cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Nal-[CAG]7(FIG.369.40) (SEQ ID NOS: 13, 40, 76);370.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-Nal-[CAG]7(SEQ ID NOS: 13, 40, 76);371.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-miniPEG2-Nal-[CAG]7 (FIG. 4Q) (SEQ ID NOS: 18, 39, 76); and372.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-Bip-[CAG]7(FIG. GG) (SEQ ID NOS: 13, 40, 76);373.wherein:374.miniPEG2is -(CH2-CH2-O)2-CH2-CO-;375.PEG2is -(CH2-CH2-O)2-CH2-CH2-CO-;376.PEG4is -(CH2-CH2-O)4-CH2-CH2-CO-;377.PEGs is -(CH2-CH2-O)8-CH2-CH2-CO-;378.PEG12is -(CH2-CH2-O)12-CH2-CH2-CO-; and379.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

27. The compound of claim 23, wherein the cargo is a PMO and the compound is selected from:381.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-PEG4-Bip-[CAG]7(FIG. 4B) (SEQ ID NOS:18, 39, 76);382.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bip-[CAG]7(SEQ ID NOS: 13, 40, 76);383.Ac-RBRRBR-K(cyclo[FGFGRGRQ] PEG4-Nal-miniPEG2-Nal-[CAG]7 (FIG. 4F) (SEQ ID NOS:87, 40, 76);384.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-rf-PEG4-Bip-[CAG]7(FIG.385.4M) (SEQ ID NOS: 13, 40, 76); Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F-[CACT]7(FIG.386.4N) (SEQ ID NOS: 18, 40, 76);387.Ac-RBRRBR-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Bta-[CAG]7(SEQ IDNOS:87, 40, 76);388.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-Nal-[CAG]7(FIG.389.40) (SEQ ID NOS: 13, 40, 76);390.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-PEG8-RF-PEG4-Nal-[CAG]7(FIG. 4P) (SEQ ID NOS: 13, 40, 76);391.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-miniPEG2-RF-miniPEG2-Nal-[CAG]7 (FIG. 4Q) (SEQ ID NOS:18, 39, 76); and392.Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-PEGi2-(2-Nal)-miniPEG2-(2-Nal)-[CAG]7(SEQ ID NOS: 18, 40, 76),393.wherein:394.miniPEG2is -(CH2-CH2-O)2-CH2-CO-;395.PEG4is -(CH2-CH2-O)4-CH2-CH2-CO-;396.PEG8is -(CH2-CH2-O)8-CH2-CH2-CO-;397.PEG12is -(CH2-CH2-O)12-CH2-CH2-CO-; and398.[CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

28. The compound of claim 23, wherein the cargo is a PMO and the compound is selected from:400.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-KF-PEG4-Bip-[CAG]7 (FIG.401.4GG);402.Ac-KKKRK-PEG2-K(cyclo[FGFGRGRQ])-PEG2-RF-PEG4-F-[CAG]7 (FIG. 4MM); and Ac-PKKKRKV-miniPEG2-K(cyclo[FGFGRGRQ])-miniPEG2-RF-PEG4-F-[CAG]7 (FIG. 4N), wherein:403.miniPEG2is -(CH2-CH2-O)2-CH2-CO-;404.PEG2is -(CH2-CH2-O)2-CH2-CH2-CO-;405.PEG4is -(CH2-CH2-O)4-CH2-CH2-CO-;406.PEG8is -(CH2-CH2-O)8-CH2-CH2-CO-;407.PEG12is -(CH2-CH2-O)12-CH2-CH2-CO-; and [CAG]7is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

29. The compound of claim 1, wherein the compound is of Formula D:409.(y'j—cargo411. 413.or a pharmaceutically acceptable salt thereof;414.wherein:415.O416.R417. 418.20isH or 'h419.wl is 0 or 1;420.al is 0 or 1,421.a2 is 1;422.a3 is 1;423.AA1 is an amino acid residue or a peptide comprising 2 to 10 amino acid residues; AA2 and AA3 are each independently an amino acid residue or a peptide comprising 1 to 6 amino acids residues, wherein AA3 comprises a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;424.j 1 and j2 are each independently an integer from 1 to 4;425.xl and x3 are each independently an integer from 1 to 14;426.n is an integer from 0 to 3;427.y is an integer from 1 to 5;428.ml is 0 or 1;429.M ' comprises -NH-,430.

431. , or a heteroaryl wherein t is an integer from 0 to 10;432.R1, R2, R3, R4, R5, R6, and R7are each independently the side chain an amino acid residue; and433.cargo comprises an oligonucleotide comprising the sequence:434.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG-3 (SEQ ID NO: 74),435.5 -CAG CAG CAG CAG CAG CAG C G CAG CAG -3 (SEQ ID NO: 73), 5'-CAG CAG CAG CAG CAG CAG CAG CAG -3' (SEQ ID NO: 72),436.5 -CAG CAG CAG CAG CAG CAG CAG -3 (SEQ ID NO: 71), 5 -CAG CAG CAG CAG CAG CAG -3 ' (SEQ ID NO: 70),437.5 -CAG CAG C G CAG CAG -3 (SEQ ID NO: 69),438.5 -CAG CAG CAG CAG -3 (SEQ ID NO: 68),439.5' -CAG CAG CAG -3, or440.5' -CAG CAG -3’.

30. The compound of claim 29, wherein the cargo is a PMO and the compound is selected from:442.Ac-K(cyclo[FGFGRGRQ])-KKKRK-PEGi2-(2-Nal)-PMO (SEQ ID NOS: 40, 76); Ac-KKK-K(cyclo[FGFGRGRQ])-RK-PEGi2-(2-Nal)-PMO (SEQ ID NOS: 40, 76); Ac-KKK-miniPEG2-K(cyclo[FGFGRGRQ])-RK-PEGi2-(2-Nal)-PMO (SEQ ID NOS: 40, 76); and Ac-K(cyclo[FGFGRGRQ])-miniPEG2-PKKKRKV-PEG8-RF-PEG4-PMO (SEQ ID NOS: 40, 76);443.wherein:444.miniPEG2is –(CH2-CH2-O)2-CH2-CO-;445.PEG4is –(CH2-CH2-O)4-CH2-CH2-CO-;446.PEG8is –(CH2-CH2-O)8-CH2-CH2-CO-;447.PEG12is –(CH2-CH2-O)12-CH2-CH2-CO-; and448.PMO is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

31. The compound of claim 1, wherein the compound is of Formula E:450.cargo452. 454.or a pharmaceutically acceptable salt thereof;455.wherein:456.R20isH or458.

459. wl is 0 or 1;460.al is 0 or 1,461.a2 is 1;462.AA1 is an amino acid residue or a peptide comprising 2 to 10 amino acid residues;463.AA2 is amino acid residue or a peptide comprising 1 to 6 amino acids residues, wherein AA2 comprises a hydrophobic amino acid residue, a hydrophilic amino acid residue, or both;464.j 1 and j2 are each independently an integer from 1 to 4;465.xl and x2 are each independently an integer from 1 to 14;466.n is an integer from 0 to 3,467.y is an integer from 1 to 5;468.ml is 0 or 1;469.M' comprises -NH-, [structure image], or a heteroaryl wherein t is an integer from 0 to 10; R1, R2, R, R4, R5, R6, and R7are each independently the side chain an amino acid residue; and470.cargo comprises an oligonucleotide comprising the sequence:471.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG-3 (SEQ ID NO: 74),472.5 -CAG CAG CAG CAG CAG CAG CAG CAG CAG -3 ' (SEQ ID NO: 73), 5 -CAG CAG CAG CAG CAG CAG CAG CAG -3 (SEQ ID NO: 72),473.5' -CAG CAG CAG CAG CAG CAG CAG -3 "(SEQ ID NO: 71),474.5 -CAG CAG CAG CAG CAG CAG -3 (SEQ ID NO: 70),475.5 -CAG C G CAG CAG CAG -3 (SEQ ID NO: 69),476.5' -CAG CAG CAG CAG -3 (SEQ ID NO: 68),477.5 -CAG CAG CAG -3, or478.5' -CAG CAG -3'.

32. The compound of claim 31, wherein the cargo is a PMO and the compound is selected from:479.Ac-PKKKRKV-miniPEG2-K(cyclo[FfFGRGRQ])-RF-PEG4-PMO (FIG. 4R) (SEQ ID NOS: 18, 39, 76); and480.Ac-KKKRK-miniPEG2-K(cyclo[FGFGRGRQ])-RF-PEG4-PMO (SEQ ID NOS: 13, 76), wherein:481.miniPEG2is –(CH2-CH2-O)2-CH2-CO-;482.PEG4is –(CH2-CH2-O)4-CH2-CH2-CO-; and483.PMO is PMO of sequence 5'-CAG-CAG-CAG-CAG-CAG-CAG-CAG-3' (SEQ ID NO: 76) and is conjugated at its 3' terminus.

33. The compound of any one of claims 1 to 4, 5 to 8, 11-16, 23 to 25, 29, or 31, wherein the oligonucleotide is a PMO.

34. A compound selected from the compounds of in FIG. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, 41, 4J, 4K, 4L, 4M, 4N, 40, 4P, 4Q, 4R, 4S, 4T, 4U, 4V, 4X, 4Y, 4Z, 4AA, 4BB, 4CC, 4DD, 4EE, 4FF, 4GG, 4HH, 411, 4JJ, 4KK, 4LL, or 4MM where RPMO is shown in FIG. 5.

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