Antisense therapeutics for treatment of repeat expansion disorders

Abstract

The present disclosure relates to compounds useful for modulation of target nucleic acids, including DNA and RNA. The present disclosure further relates to methods for treatment of repeat expansion disorders, which can include administration of compounds provided herein that can bind pathogenic nucleotide repeats in DNA or RNA.

Description

WSGR Docket No. 65156-703.601ANTISENSE THERAPEUTICS FOR TREATMENT OF REPEAT EXPANSION DISORDERSCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 725,241, filedNovember 26, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Peptide nucleic acids (PNAs) are nucleobase-bearing polymeric constructs with repeating units based on a N-(2-aminoethyl)glycine scaffold. PNAs can mimic the arrangement of nucleobases in nucleic acids and can be tailored to hybridize with DNA or RNA with high affinity and specificity. PNAs have been used as biosensors, antivirals, antiparasitics, antibacterials, and therapeutic agents for treatment of genetic disorders.INCORPORATION BY REFERENCE

[0003] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually.SUMMARY

[0004] In some embodiments, the present disclosure provides a compound of formula (VI), or a pharmaceutically-acceptable salt or ionized form thereof:N-Terminus - L 1 — PEP 1— L 2 - PNA 1- --Terminus(VI)wherein:JV-Terminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent;- Z is -(Ul)(X5)-xY-(X8)(X9)-YYx-(X13)(X14)(X15)(X16)-Y-(U2)-;- U1 is -Yx-(X3)(X4)-, -x-(X3)(X4)-, -(X3)(X4)-, -(X4)-, or absent;U2 is -x-(X19)-, -x-, or absent;- each of X3, X4, X5, X8, X9, XI 2, XI 3, XI 4, XI 5, XI 6, and X19 is independently Y or x; each Y is independentlyWSGR Docket No. 65156-703.601 each x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH.

[0005] In some embodiments, the present disclosure provides a compound of formula (Ila), or a pharmaceutically-acceptable salt or ionized form thereof:N-Terminus“ Z— PNA 2-L 3— PEP 2— L 4 — C-Terminus (na; wherein: '-Tcrminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andZ is -YY(x)mYY-, -[YYxxxx]t-, -(x)u(Y)kx(Y)k(x)u-, -YxYxxY(x)aYxYxx-, -[xYxxY]v-, -[Yxx]p-, - [YxxYxxxYxxx]n-, -[Yxxx]q-, -[YxxxYxx]rY-, -(Y)w(x)fYYY(x)j(Y)w-, -xYxYxxYxY-, - YxYYx-, -(x)bY(x)s, - xxYxxYxYxx-, -Yx(Yxx)bY-, -YxYxYxxYxxYxYx-, -xYxYYYxY-, - YxxYYxYY-, -YYxYYxxY-, or -YxxYYxxY-; wherein:palphal each Y is independently each x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralrhalis H; or each R1is H and each RalPhalis independently alkyl substituted with aWSGR Docket No. 65156-703.601 group that bears a positive charge at physiological pH; each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH; b, m, u, and q are each independently 4, 5, 6, 7, 8, or 9; s is 3, 4, 5, 6, 7, or 8; a and n are each independently 1, 2, or 3; w, r, v, and t are each independently is 2, 3, 4, or 5; k is 3, 4, or 5; each f and j is independently 4, 5, or 6; and p is 4, 5, 6, 7, 8, or 9.

[0006] In some embodiments, the present disclosure provides a compound of formula (IV), or a pharmaceutically-acceptable salt or ionized form thereof:usnv. wherein:V-Terminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andwherein: each RNis independently methyl substituted with a heterocycle; each RGis independently alkyl substituted with a group that bears a positive charge at physiological pH or hydroxyalkyl, and each Ralphais H; or each RGis H and each Ralphais independently alkyl substituted with a group that bears a positive charge at physiological pH or hydroxyalkyl; and the number of units with variables defined independently is at least 10, wherein in 40-60% of the units with variables defined independently, either: (a) each RGis independently hydroxyalkyl and each Ralphais H, or (b) each RGis H and each Ralphais independently hydroxyalkyl; and in the remainder of the units with variables defined independently, either: (a) each RGisWSGR Docket No. 65156-703.601 independently a group that bears a positive charge at physiological pH and Ralrhais H, or (b) each RGis H and each RalPhais independently a group that bears a positive charge at physiological pH.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e.g. natural, modified, or non-natural nucleobases), or hydrogen.

[0008] FIG. 2 is a chart summarizing mHTT and wtHTT protein levels observed in fibroblasts treated with 2 pM Compounds 3-64.

[0009] FIG. 3 is a chart summarizing mHTT and wtHTT protein levels observed in fibroblasts treated with 10 pM Compounds 1-64.

[0010] FIG. 4 provides a chart summarizing allele specificity for Compounds 3-64 at 2 pM (top panel) and Compounds 1-64 at 10 pM (bottom panel).

[0011] FIG. 5 provides a chart summarizing the product of allele specificity and efficacy for Compounds 3-64 at 2 pM (top panel) and Compounds 1-64 at 10 pM (bottom panel).

[0012] FIG. 6 is an immunoblot for TATA box binding protein (TBP) in fibroblasts treated with Compounds 8, 12, and 13.

[0013] FIG. 7 is an immunoblot for TATA box binding protein (TBP) in fibroblasts treated with Compounds 24, 27, and 29.

[0014] FIG. 8 is a chart that summarizes TBP / vinculin ratios in fibroblasts treated with Compounds 8,12, and 13.

[0015] FIG. 9 is a chart that summarizes TBP / vinculin ratios in fibroblasts treated with Compounds 24, 27, and 29.

[0016] FIG. 10A and FIG. 10B are charts summarizing mHTT (FIG. 10A) and wtHTT (FIG. 10B) protein levels observed in fibroblasts treated with 5 pM Compounds 3, 13, 47, 60, and 76-83.

[0017] FIG. 11 provides a chart summarizing allele specificity for Compounds 3, 13, 47, 60, and 76-83 at 5 pM, calculated from the values presented in FIG. 10A and FIG. 10B.

[0018] FIG. 12 is a chart summarizing cell viability for fibroblasts treated with Compounds 3, 13, 47, 60, and 76-83 at 5 pM in terms of color intensity of Alamar Blue dye.

[0019] FIG. 13A and FIG. 13B are charts illustrating the diameter (nm) (FIG. 13A) and mass area (%) (FIG. 13B) of particles of Compound 60 either in water or an aqueous L-histidine-dextrose solution as measured by dynamic light scattering.

[0020] FIGs 14A-D are charts illustrating the mass area (%) (FIG. 14B (peak 1) and FIG. 14D (peak 2)) and diameter (nm) (FIG. 14A (peak 1) and FIG. 14C (peak 2)) of particles of Compound 60 either in water or an aqueous L-histidine-dextrose solution as measured by dynamic light scattering at 1, 2, 3, or 4 weeks of storage at -80 °C, 4 °C, or 27 °C.WSGR Docket No. 65156-703.601DETAILED DESCRIPTION

[0021] Compounds disclosed herein can be effective for the modulation of target nucleic acids, such as RNA or DNA. Such compounds can be effective for binding to nucleic acid molecules containing mutations associated with a disease, such as, for example, a repeat expansion disease.

[0022] Huntington’s disease is a repeat expansion disease associated with a defective Huntingtin (HTT) gene on chromosome 4. Expansion of CAG trinucleotide repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the HTT gene results in an abnormal mutant protein (mHTT), which can cause gradual neuronal cell damage. The progressive and heritable increase in length of CAG repeats encode a polyglutamine tract in the coding region of the HTT gene. These CAG repeats can increase in number from one generation to another. The normal allele of the HTT gene can comprise fewer than 36 CAG repeats, whereas the mutant allele can comprise more than 36 repeats. Many HD patients carry one normal allele and a mutant disease-causing allele. Normal or wild type HTT is widely expressed and important for cell signaling, transcriptional regulation, molecular trafficking, and axonal transport, modulating brain-derived neurotrophic factor (BDNF) production. Aberrant accumulation of CAG repeats can confer a toxic gain-of-function phenotype, causing the protein to aggregate and form protein deposits (inclusion bodies). Neuronal loss can start in the striatum and progress to the cortex. Disease severity generally reflects the extent of expanded repeats in the mutant HTT protein.

[0023] Provided herein are compounds, compositions, and methods for the treatment of HD. These compounds can, for example, reduce or inhibit expression of the disease-causing HTT gene by targeting nucleic acids associated with the mutant HTT expression, e.g., RNA or DNA precursors of mutant HTT. For example, the compounds can bind to nucleic acid molecule associated with HD, thereby reducing mRNA expression or protein expression of the disease-causing HTT gene.

[0024] Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant repeat expansion disorder characterized by progressive muscle wasting and weakness. DM1 can also affect the central nervous system (CNS) and heart. A genetic mutation results in generalized mis-splicing of transcripts and haploinsufficiency of the DMPK protein which both contribute to the disease.

[0025] DM1 is caused by an expansion of CTG nucleic acid repeats in the DMPK gene that produce a hairpin structure in transcribed DMPK mRNA (as CUG repeats in the 3' UTR of the transcript). The hairpin structure sequesters splice regulators and results in mis-splicing of multiple gene transcripts. For example, the hairpins can form aggregates that sequester MBNL1 and / or MBNL2 transcripts, resulting in widespread mis-splicing of pre-mRNAs. Furthermore, binding of splice regulators and aggregation can trap the mutant DMPK mRNA in the nucleus and result in DMPK protein haploinsufficiency, which can exacerbate the CNS and cardiac symptoms that can characterize DM1. Mis-spliced transcripts can also result in altered protein products that are dysfunctional.

[0026] Mild DM1 is characterized by cataract development, mild myotonia (sustained muscle contraction), and normal lifespan. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataract, and often cardiac conduction abnormalities. Adults with classic DM1 can becomeWSGR Docket No. 65156-703.601 physically disabled and can have a shortened life span. Congenital DM1 is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death. Intellectual disability is common. The severity of DM1 can correlate with the number of CTG nucleic acid repeats in the DMPK gene.

[0027] Also provided herein are compounds, compositions, and methods for the treatment of DM1.These compounds can, for example, reduce or inhibit expression of the disease-causing DM1 gene by targeting nucleic acids associated with the mutant DM1 gene, e.g., RNA or DNA. mRNAs with a CUG repeat expansion can fold into a hairpin structure with a double stranded region containing GC base pairs and bulged, unpaired U residues. In some embodiments, a compound disclosed herein opens a doublestranded RNA transcript that contains a CUG repeat, sterically displaces a Muscleblind Like Splicing Regulator (e.g., MBNL1 and / or MBNL2) that is sequestered by the transcript, and / or resolves splicing to form a normal or closer to normal complement of mRNAs or proteins.Compounds of the Disclosure.

[0028] Described herein are compounds for the modulation of nucleic acids bearing mutations associated with a disease, including repeat expansion diseases such as Huntington’s disease and Myotonic Dystrophy type 1. Compounds disclosed herein include those comprising a peptide nucleic acid domain. Peptide nucleic acids are oligonucleotide analogues that comprise a chain of repeating N-(2-aminoethyl)- glycine units linked by peptide bonds, where the glycyl nitrogen of one or more units is functionalized with an alkylene or acyl group bearing a cyclic moiety, such as a nucleobase. Peptide nucleic acids can optionally comprise substitution on the N-(2-aminoethyl)-glycine backbone, for example:where substituents R“, Rp, R7, are alpha, beta, and gamma substituents, respectively.

[0029] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically-acceptable salt or ionized form thereof:N-Terminus“ Z— PNA 2-L 3— PEP 2— L 4 — C-Terminusmwherein:N-Terminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2;PEP1 and PEP2 are each independently a peptide sequence or absent;PNA 1 and PNA2 are each independently a peptide nucleic acid sequence or absent;LI, L2, L3, and L4 are each independently a linker group or absent; andWSGR Docket No. 65156-703.601Z is -YY(x)mYY-, -[YYxxxx]t-, -(x)u(Y)kx(Y)k(x)u-, -YxYxxY(x)aYxYxx-, -[xYxxY]v-, -[Yxx]p-, -[YxxYxxxYxxx]n-, -[Yxxx]q-, or -[YxxxYxx]rY-, wherein: each Y is independently an alpha- or gamma-substituted peptide nucleic acid residue; each x is independentlyeach R2is independently methyl substituted with a heterocycle; m, u, and q are each independently 4, 5, 6, 7, 8, or 9; a and n are each independently 1, 2, or 3; r, v, and t are each independently is 2, 3, 4, or 5; k is 3, 4, or 5; and p is 5, 6, 7, 8, or 9.

[0030] In some embodiments, each Y is independentlywherein eachR1is independently alkyl that is unsubstituted or substituted and Ralphalis H, or each R1is H and each Ralphal-sindependently alkyl that is unsubstituted or substituted.

[0031] In some embodiments, each Y is independently

[0032] In some embodiments, each R1is independently guanidinoalkyl or hydoxyalkyl, and each Ralphalis H; or each R1is H and each Ralrhalis independently guanidinoalkyl or hydoxyalkyl.

[0033] In some embodiments, each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPhalis H; or each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH. In some embodiments, each R1is independently guanidinoalkyl, and each RalPhalis H; or each R1is H and each Ralphal-sindependently guanidinoalkyl. In some embodiments, each R1is independently 3- guanidinoprop-l-yl or 4-guanidinobut-l-yl, and each RalPhalis H; or each R1is H and each RalPhalis independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl. In some embodiments, each R1is 4- guanidinobut-l-yl, and each RalPhalis H; or each R1is H and each RalPhalis 3-guanidinoprop-l-yl. In some embodiments, each R1is 4-guanidinobut-l-yl, and each RalPhalis H. In some embodiments, each R1is H and each RalPhalis 3-guanidinoprop-l-yl.

[0034] In some embodiments, each R1is independently hydoxyalkyl, and each RalPhalis H; or each R1is H and each RalPhalis independently hydoxyalkyl. In some embodiments, each R1is hydroxymethyl, and each RalPhalis H; or each R1is H and each RalPhalis hydroxymethyl. In some embodiments, each R1isWSGR Docket No. 65156-703.601 hydroxymethyl, and each Ralphalis H. In some embodiments, each R1is H and each Ralphalis hydroxymethyl.

[0035] In some embodiments, the present disclosure provides a compound of formula (II), or a pharmaceutically-acceptable salt or ionized form thereof:usnwherein: '-Tcrminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2;PEP1 and PEP2 are each independently a peptide sequence or absent;PNA 1 and PNA2 are each independently a peptide nucleic acid sequence or absent;LI, L2, L3, and L4 are each independently a linker group or absent; andZ is -YY(x)mYY-, -[YYxxxx]t-, -(x)u(Y)kx(Y)k(x)u-, -YxYxxY(x)aYxYxx-, -[xYxxY]v-, -[Yxx]p-, -[YxxYxxxYxxx]n-, -[Yxxx]q-, or -[YxxxYxx]rY-, wherein: each Y is independentlyeach x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralrhalis H; or each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH; each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPha2is H; or each R3is H and each RalPha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH; m, u, and q are each independently 4, 5, 6, 7, 8, or 9; a and n are each independently 1, 2, or 3; r, v, and t are each independently is 2, 3, 4, or 5; k is 3, 4, or 5; and p is 5, 6, 7, 8, or 9.WSGR Docket No. 65156-703.601

[0036] In some embodiments, each Y is independentlysome embodiments, each x is independently

[0037] In some embodiments, Z is -YY(x)mYY-. In some embodiments, m is 4 or 5. In some embodiments, Z is -YYxxxxYY-. In some embodiments, Z is -YYxxxxxYY-.

[0038] In some embodiments, Z is -[YYxxxx]t-. In some embodiments, t is 2. In some embodiments, Z is-YY xxxxYY xxxx- .

[0039] In some embodiments, Z is -(x)u(Y)kx(Y)k(x)u-. In some embodiments, each k is 3. In some embodiments, Z is -(x)uYYYxYYY(x)u-, wherein each u is 5, 6, or 7. In some embodiments, each u is independently 5, 6, or 7. In some embodiments, Z is -xxxxxYYYxYYYxxxxx-. In some embodiments, Z is -xxxxxxYYYxYYYxxxxxx-. In some embodiments, Z is -xxxxxxxYYYxYYYxxxxxxx-.

[0040] In some embodiments, Z is -YxYxxY(x)aYxYxx-. In some embodiments, a is 1 or 2. In some embodiments, Z is -YxYxxYxxYxYxx-. In some embodiments, Z is -YxYxxYxYxYxx-.

[0041] In some embodiments, Z is -[xYxxY]v-. In some embodiments, v is 2. In some embodiments, Z is -xY xxY xY xxY - .

[0042] In some embodiments, Z is -[Yxx]p-. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, Z is -YxxYxxYxxYxxYxxYxx-. In some embodiments, p is 8. In some embodiments, Z is -YxxYxxYxxYxxYxxYxxYxx-. In some embodiments, Z is -Y xxY xxY xxY xxY xxY xxY xxY xx- .

[0043] In some embodiments, Z is -[YxxYxxxYxxx]n-. In some embodiments, n is 2. In some embodiments, Z is -YxxYxxxYxxxYxxYxxxYxxx-.

[0044] In some embodiments, Z is -[Yxxx]q-. In some embodiments, q is 6. In some embodiments, Z is -Y xxxY xxxY xxxY xxxY xxxY xxx- .

[0045] In some embodiments, Z is -[YxxxYxx]rY-. In some embodiments, r is 2. In some embodiments, Z is -YxxxYxxYxxxYxxY-.

[0046] In some embodiments, -PNA1-Z-PNA2- is -YYxxxYYxxxxYYxxxxYY-. In some embodiments, -PNA1-Z-PNA2- is -YYxxxxxYYxxxxYYxxxxYY-. In some embodiments, -PNA1-Z-PNA2- is - YYxxxxxYYxxxxxYYxxxxxYY-. In some embodiments, -PNA1-Z-PNA2- is - YxxxxxYYYxYYYxxxxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxxxxxxYYYxYYYxxxxxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxxxxxxxYYYxYYYxxxxxxxY-. In some embodiments, -PNA1-Z-PNA2- is -YxYxxYxxYxYxxYxxY- . In some embodiments, -PNA1-Z-PNA2- is -YxYxxYxYxxYxYxYxY-. In some embodiments, -PNA1- Z-PNA2- is -YxxYxxYxxYxxYxxYxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxYxYxxYxYxYxxYxYxY-. In some embodiments, -PNA1-Z-PNA2- is -WSGR Docket No. 65156-703.601YxxxYxxYxxxYxxYxxYxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxYxxYxxYxxYxxYxxYxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxYxxYxYxxYxxYxYxYxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxxYxxxYxxxYxxYxxxYxxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxxxYxxYxxYxxYxxYxxYxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxYxxYxxYxxYxxYxxYxxYxY In some embodiments, -PNA1-Z-PNA2- is - YxxxYxxxYxxxYxxxYxxxYxxxY-. In some embodiments, -PNA1-Z-PNA2- is - YxxxYxxYxxxYxxYxxYxxYxxxY-. In some embodiments, -PNA1-Z-PNA2- is -Y xxY xxY xxY xxY xxY xxY xxY xxY - .

[0047] In some embodiments, the present disclosure provides a compound of formula (Ila), or a pharmaceutically-acceptable salt or ionized form thereof:N-Terminus— Z— PNA 2-L 3— PEP 2— L 4 — C-Terminusmtira .j, wherein:A-Terminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andZ is -YY(x)mYY-, -[YYxxxx]t-, -(x)u(Y)kx(Y)k(x)u-, -YxYxxY(x)aYxYxx-, -[xYxxY]v-, -[Yxx]p-, - [YxxYxxxYxxx]n-, -[Yxxx]q-, -[YxxxYxx]rY-, -(Y)w(x)fYYY(x)j(Y)w-, -xYxYxxYxY-, - YxYYx-, -(x)bY(x)s, - xxYxxYxYxx-, -Yx(Yxx)bY-, -YxYxYxxYxxYxYx-, -xYxYYYxY-, - YxxYYxYY-, -YYxYYxxY-, or -YxxYYxxY-; wherein:nalphal each Y is independently each x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPhalis H; or each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH;WSGR Docket No. 65156-703.601 each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH; b, m, u, and q are each independently 4, 5, 6, 7, 8, or 9; s is 3, 4, 5, 6, 7, or 8; a and n are each independently 1, 2, or 3; w, r, v, and t are each independently is 2, 3, 4, or 5; k is 3, 4, or 5; and each f and j is independently 4, 5, or 6; p is 4, 5, 6, 7, 8, or 9. / R1V2Hn\ j / H I H2] / II | s-H-N-C-C - N-C — C- H-\ A * /

[0048] In some embodiments, each Y is independently paiphai jnsome embodiments, each x is independently

[0049] In some embodiments, Z is -YY(x)mYY-. In some embodiments, m is 4, 5, 6, 7, 8, or 9. In some embodiments, m is 4 or 5. In some embodiments, Z is -YYxxxxYY-. In some embodiments, PNA1-Z- PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 5. In some embodiments, PNA1-Z- PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 6. In some embodiments, Z is - YYxxxxxYY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 7. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.WSGR Docket No. 65156-703.601

[0050] In some embodiments, Z is -[YYxxxx]t-. In some embodiments, t is 2, 3, 4, or 5. In some embodiments, t is 2. In some embodiments, Z is -YYxxxxYYxxxx-. In some embodiments, PNA1-Z- PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 5. In some embodiments, PNA1-Z- PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 6. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D- Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0051] In some embodiments, Z is -(x)u(Y)kx(Y)k(x)u-. In some embodiments, each k is independently 3, 4, or 5. In some embodiments, each k is 3. In some embodiments, u is 4, 5, 6, 7, 8, or 9. In some embodiments, u is 5, 6, 7. In some embodiments, Z is -(x)uYYYxYYY(x)u-, wherein each u is 5, 6, or 7. In some embodiments, each u is independently 5, 6, or 7. In some embodiments, Z is - xxxxxYYYxYYYxxxxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 8. In some embodiments, Z is -xxxxxxYYYxYYYxxxxxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 9. In some embodiments, Z is -xxxxxxxYYYxYYYxxxxxxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 10. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PNA2 is Y. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. InWSGR Docket No. 65156-703.601 some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N- Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0052] In some embodiments, Z is -YxYxxY(x)aYxYxx-. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, Z is -YxYxxYxxYxYxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 11. In some embodiments, Z is -YxYxxYxYxYxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 14. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D- Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C- Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0053] In some embodiments, Z is -[xYxxY]v-. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5. In some embodiments, Z is - xYxxYxYxxY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 12. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 18. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 45. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 47. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 51. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10WSGR Docket No. 65156-703.601 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D- Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0054] In some embodiments, Z is -[Yxx]p-. In some embodiments, p is 4. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 72. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 73. In some embodiments, p is 5, 6, 7, 8, or 9. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, Z is - YxxYxxYxxYxxYxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 55. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 59. In some embodiments, Z is -YxxYxxYxxYxxY xxYxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 14. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 17. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 20. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 21. In some embodiments, p is 8. In some embodiments, Z is -YxxYxxYxxYxxYxxYxxYxx-. In some embodiments, Z is -YxxYxxY xxYxxYxxY xxYxxYxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 24. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is 1 or 2 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is -Yxxx-. In some embodiments, PNA1 is -Yx-. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is Y. In some embodiments, PNA2 is -Yx-. In some embodiments, PNA2 is -YxY-. In some embodiments, PNA2 is -WSGR Docket No. 65156-703.601Yxxx-. In some embodiments, PNA2 is -YxxxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D- Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N- Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0055] In some embodiments, Z is -[YxxYxxxYxxx]n-. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, Z is -YxxYxxxYxxx-. In some embodiments, PNA1-Z- PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 43. In some embodiments, Z is - YxxYxxxYxxxYxxYxxxYxxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 19. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -YxxY-. In some embodiments, PNA2 is Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0056] In some embodiments, Z is -[Yxxx]q-. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, Z is -YxxxYxxxYxxxYxxxYxxxYxxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 22. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In someWSGR Docket No. 65156-703.601 embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0057] In some embodiments, Z is -[YxxxYxx]rY-. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, Z is - YxxxYxxYxxxYxxY-. In some embodiments, -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 23. In some embodiments, -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 16. In some embodiments, -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 54. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 15 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, PNA1 is -Yxx-. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 15 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -xxY xxY-. In some embodiments, PNA2 is -xxYxxYxxxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.WSGR Docket No. 65156-703.601

[0058] In some embodiments, Z is -(Y)w(x)fYYY (x)j(Y)w-. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, f is 4. In some embodiments, f is 5. In some embodiments, f is 6. In some embodiments, ] is 4. In some embodiments,] is 5. In some embodiments,] is 6. In some embodiments, Z is YY(x)5YYY(x)6YY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 62. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO: 62. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 64. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO: 64. In some embodiments, Z is YYY(x)4YYY(x)5YYY-. In some embodiments, PNA1-Z- PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 63. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO: 63. In some embodiments, Z is YY(X)4YYY(X)4YY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 49. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO: 49. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 50. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO: 50. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA 1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D- Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N- Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0059] In some embodiments, Z is -xYxYxxYxY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 36. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 57. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 60. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA 1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In someWSGR Docket No. 65156-703.601 embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0060] In some embodiments, Z is -YxYYx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 37. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 38. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 39. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 40. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 76. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 77. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0061] In some embodiments, Z is -(x)bY(x)s-. In some embodiments, b is 4. In some embodiments, b is 5. In some embodiments, b is 6. In some embodiments, s is 3. In some embodiments, s is 4. In some embodiments, s is 5. In some embodiments, s is 6. In some embodiments, s is 7. In some embodiments, Z is -(X)4Y(X)4-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 48. In some embodiments, Z is -(x) Y(x)3-. In some embodiments, Z is -(x) Y(x)7-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 58. In someWSGR Docket No. 65156-703.601 embodiments, Z is -(x)4Y(x)5-. In some embodiments, Z is -(x)4Y(x)e-. In some embodiments, Z is - (x) Y(x)7-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 61. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is -YxYx-. In some embodiments, PNA1 is -YxxY-. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -YxYx-. In some embodiments, PNA2 is - YxxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0062] In some embodiments, Z is -xxYxxYxYxx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 35. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 44. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is -Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is Y. In some embodiments, PNA2 is - YxxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.WSGR Docket No. 65156-703.601

[0063] In some embodiments, Z is -Yx(Yxx)bY-. In some embodiments, b is 4. In some embodiments, b is 5. In some embodiments, b is 6. In some embodiments, Z is -Yx(Yxx)4Y-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 52. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -xY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0064] In some embodiments, Z is -YxY xYxxYxxYxYx-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 56. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -YxxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D- Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N- Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0065] In some embodiments, Z is -xYxYYYxY -. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 71. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1WSGR Docket No. 65156-703.601 independently has a structure according to x or Y. In some embodiments, PNA1 is -YxY-. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -xYxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N- Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0066] In some embodiments, Z is -YxxYYxYY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 74. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 75. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 76. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is -xxYYx-. In some embodiments, PNA1 is -YxxYYx-. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -xxYx-. In some embodiments, PNA2 is -xxYxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0067] In some embodiments, Z is -YYxYYxxY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 74. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 75. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 76. In some embodiments, PNA1 is a peptide nucleicWSGR Docket No. 65156-703.601 acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is -Yxx-. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -xxYx-. In some embodiments, PNA2 is - xxYxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0068] In some embodiments, Z is -YxxYYxxY-. In some embodiments, PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 77. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA1 independently has a structure according to x or Y. In some embodiments, PNA1 is -Yx-. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, each residue of PNA2 independently has a structure according to x or Y. In some embodiments, PNA2 is -xxYx-. In some embodiments, PNA2 is - xxYxY-. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0069] In some embodiments, each residue of PEP 1 comprises a side chain that is positively charged at physiological pH. In some embodiments, each residue of PEP2 comprises a side chain that is positively charged at physiological pH.WSGR Docket No. 65156-703.601

[0070] In some embodiments, the present disclosure provides a compound of formula (III), or a pharmaceutically-acceptable salt or ionized form thereof:wherein: '-Tcrminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andZ is -(WY)a-, -(WWY)b-, or -WWYWW-; wherein: each Y is independentlyeach W is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralrhalis H; or each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH; each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPha2is H; or each R3is H and each RalPha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH; a is 2-20; and b is 1-20.

[0071] In some embodiments, a is 5-10. In some embodiments, a is 7, 8, or 9.

[0072] In some embodiments, b is 2-10. In some embodiments, b is 2, 3, 4, 5, or 6. In some embodiments, b is 6.WSGR Docket No. 65156-703.601

[0073] In some embodiments, each Y is independentlysome embodiments, each W is independently

[0074] In some embodiments, Z is -WYWYWYWYWYWYWY-. In some embodiments, Z is - WYWYWYWYWYWYWYWY-. In some embodiments, Z is -WYWYWYWYWYWYWYWYWY-.In some embodiments, Z is -WWYWWY-. In some embodiments, Z is -WWYWWYWWYWWYWWYWWY-.

[0075] In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWY-. In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - WYWYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWYWWYWWYWYWYWWY-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWWYWWYWWYWWYWWYWY- .

[0076] In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWY-. In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - WYWYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWYWWYWWYWYWYWWY-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWWYWWYWWYWWYWWYWY-.

[0077] In some embodiments, each R1is independently aminobut-l-yl, 3 -aminoprop- 1-yl, 1-H-imidazol- 4-ylmethyl, l-H-indol-3-ylmethyl, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl, and each Ralphalis H, or each R1is H and each Ralrhalis independently aminobut-l-yl, 3-aminoprop-l-yl, l-H-imidazol-4- ylmethyl, l-H-indol-3-ylmethyl, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.

[0078] In some embodiments, each R1is independently guanidinoalkyl, and each RalPhalis H, or each R1is H and each RalPhalis independently guanidinoalkyl. In some embodiments, each R1is independently Ci- 4guanidinoalkyl, and each RalPhalis H, or each R1is H and each RalPhalis independently Ci- 4guanidinoalkyl. In some embodiments, each R1is independently 4-guanidinobut-l-yl, and each RalPhalis H, or each R1is H and each RalPhalis independently 3-guanidinoprop-l-yl.

[0079] In some embodiments, each R1is independently 4-guanidinobut-l-yl, and each RalPhalis H.

[0080] In some embodiments, each R1is independently guanidinoalkyl, and each RalPhalis H. In some embodiments, each R1is independently Ci-4guanidinoalkyl, and each RalPhalis H. In some embodiments, each R1is independently 4-guanidinobut-l-yl, and each RalPhalis H.

[0081] In some embodiments, each R1is H, and each RalPhalis independently aminobut-l-yl, 3- aminoprop-l-yl, l-H-imidazol-4-ylmethyl, l-H-indol-3-ylmethyl, 3-guanidinoprop-l-yl, or 4- guanidinobut- 1 -yl .WSGR Docket No. 65156-703.601

[0082] In some embodiments, each R1is H, and each Ralfhalis independently guanidinoalkyl. In some embodiments, each R1is H, and each RalPhalis independently Ci-4guanidinoalkyl. In some embodiments, each R1is H, and each RalPhalis independently 3-guanidinoprop-l-yl.

[0083] In some embodiments, each R3is independently hydroxyalkyl or H, and each RalPha2is H, or each R3is H and each RalPha2is independently hydroxyalkyl or H. In some embodiments, each R3is independently Ci-4hydroxyalkyl or H, and each RalPha2is H, or each R3is H and each RalPha2is independently Ci-4hydroxyalkyl or H. In some embodiments, each R3is independently Ci-4hydroxyalkyl, and each RalPha2is H, or each R3is H and each RalPha2is independently Ci-4hydroxyalkyl.

[0084] In some embodiments, each R3is independently hydroxymethyl or H, and each RalPha2is H, or each R3is H and each RalPha2is independently hydroxymethyl or H. In some embodiments, each R3is independently hydroxymethyl, and each RalPha2is H, or each R3is H and each RalPha2is independently hydroxymethyl. In some embodiments, each R3and RalPha2is H.

[0085] In some embodiments, each R3is independently hydroxyalkyl or H, and each RalPha2is H. In some embodiments, each R3is independently Ci-4hydroxy alkyl or H, and each RalPha2is H. In some embodiments, each R3is independently Ci-4hydroxyalkyl, and each RalPha2is H.

[0086] In some embodiments, each R3is independently hydroxymethyl or H, and each RalPha2is H. In some embodiments, each R3is independently hydroxymethyl, and each RalPha2is H.

[0087] In some embodiments, the present disclosure provides a compound of formula (IV), or a pharmaceutically-acceptable salt or ionized form thereof:wherein:V-Terminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andwherein: each RNis independently methyl substituted with a heterocycle; each RGis independently alkyl substituted with a group that bears a positive charge at physiological pH or hydroxyalkyl, and each Ralphais H; or each RGis H and each Ralphais independently alkyl substituted with a group that bears a positive charge at physiological pH or hydroxyalkyl; andWSGR Docket No. 65156-703.601 the number of units with variables defined independently is at least 10, wherein in 40-60% of the units with variables defined independently, either: (a) each RGis independently hydroxyalkyl and each Ralphais H, or (b) each RGis H and each Ralphais independently hydroxyalkyl; and in the remainder of the units with variables defined independently, either (a) each RGis independently a group that bears a positive charge at physiological pH and Ralrhais H, or (b) each RGis H and each RalPhais independently a group that bears a positive charge at physiological pH.

[0088] In some embodiments, each hydroxyalkyl is hydroxymethyl. In some embodiments, each group that bears a positive charge at physiological pH is independently guanidinoalkyl. In some embodiments, each group that bears a positive charge at physiological pH is independently Ci.4guanidinoalkyl.

[0090] In some embodiments, in 40-60% of the units with variables defined independently, each RGis independently hydroxyalkyl and each Ralphalis H; and in the remainder of the units with variables defined independently, each RGis H and each Ralrhalis independently a group that bears a positive charge at physiological pH.

[0091] In some embodiments, in 40-60% of the units with variables defined independently, each RGis independently hydroxyalkyl and each RalPhais H; and in the remainder of the units with variables defined independently, each RGis H and each RalPhais independently guanidinoalkyl.

[0092] In some embodiments, in 40-60% of the units with variables defined independently, each RGis independently Ci.4hydroxyalkyl and each RalPhais H; and in the remainder of the units with variables defined independently, each RGis H and each RalPhais independently Ci.4guanidinoalkyl.

[0093] In some embodiments, in 40-60% of the units with variables defined independently, each RGis hydroxymethyl and each RalPhais H; and in the remainder of the units with variables defined independently, each RGis H and each RalPhais 3-guanidinoprop-l-yl.

[0094] Physiological pH can vary according to the desired target tissue. In some embodiments, physiological pH is about 7 to about 7.8. In some embodiments, physiological pH is about 7 to about 7.1. In some embodiments, physiological pH is about 7.37 to about 7.42.

[0095] In some embodiments, the number of units with variables defined independently is at least 14. the number of units with variables defined independently is at least 17. In some embodiments, the number of units with variables defined independently is at least 19. In some embodiments, the number of units with variables defined independently is from 10 to 300. In some embodiments, the number of units with variables defined independently is from 10 to 250. In some embodiments, the number of units with variables defined independently is from 10 to 200. In some embodiments, the number of units with variables defined independently is from 10 to 100. In some embodiments, the number of units withWSGR Docket No. 65156-703.601 variables defined independently is from 10 to 50. In some embodiments, the number of units with variables defined independently is from 10 to 30. In some embodiments, the number of units with variables defined independently is from 10 to 20. In some embodiments, the number of units with variables defined independently is from 15 to 30.

[0096] In some embodiments, Z is -(WY)a-, -(WWY)b-, or -WWYWW-, wherein: each Y is independentlyeach W is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH;R3is independently hydroxyalkyl and each Ralpha2is H, or each R3is H and each Ralpha2is independently hydroxyalkyl; a is 2-20; and- b is 1-20.

[0097] In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWY-. In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - WYWYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWYWWYWWYWYWYWWY-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWWYWWYWWYWWYWWYWY- .

[0098] In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWY-. In some embodiments, -PNA1-Z-PNA2- is -WYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - WYWYWYWYWYWYWYWYWYW-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWYWWYWWYWYWYWWY-. In some embodiments, -PNA1-Z-PNA2- is - YWYWWYWWYWWYWWYWWYWWYWY-.

[0099] In some embodiments, Z is a peptide nucleic acid sequence, wherein each residue of the peptide nucleic acid sequence has a structure that is independently Y or W, wherein:WSGR Docket No. 65156-703.601 each Y is independentlyeach W is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; andR3is independently hydroxyalkyl and each Ralrha2is H, or each R3is H and each RalPha2is independently hydroxyalkyl.

[0100] In some embodiments, Z is -WYWYWYWYWYWYWY-. In some embodiments, Z is - WYWYWYWYWYWYWYWYW-. In some embodiments, Z is - WYWYWYWYWYWYWYWYW'fW-. In some embodiments, Z is - YWYWWYWYWWYWWYWYWYWWY-. In some embodiments, Z is - YWYWWYWWYWWYWWYWWYWWYWY- .

[0101] In some embodiments, the present disclosure provides a compound of formula (V), or a pharmaceutically-acceptable salt or ionized form thereof:usVx wherein: '-Tcrminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andZ is a peptide nucleic acid sequence.

[0102] In some embodiments, PEP1 is the peptide sequence. In some embodiments, PEP1 is a lysine residue. In some embodiments, PEP1 is a D-lysine residue (D-Lys). In some embodiments, PEP1 is an arginine residue. In some embodiments, PEP1 is a D-arginine residue (D-Arg). In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP2 is the peptide sequence. In some embodiments, PEP2 is absent. In some embodiments, PEP2 is a lysine residue. In some embodiments, PEP2 is a D-WSGR Docket No. 65156-703.601 lysine residue. In some embodiments, PEP2 is an arginine residue. In some embodiments, PEP2 is a D- arginine residue (D-Arg).

[0103] In some embodiments, PEP1 is absent, and N-Terminus is acyl. In some embodiments, PEP1 is the peptide sequence, and N-Terminus is acyl. In some embodiments, N-Terminus is Ci-eacyl. In some embodiments, PEP1 is absent, and N-Terminus is Ci-eacyl. In some embodiments, PEP1 is absent, and N- Terminus is acetyl. In some embodiments, PEP1 and PEP2 are each absent, and N-Terminus is acyl. In some embodiments, PEP1 and PEP2 are each absent, and N-Terminus is Ci-4acyl. In some embodiments, PEP1 and PEP2 are each absent, and N-Terminus is acetyl. In some embodiments, PEP1 and PEP2 are each D-Lys, and N-Terminus is acetyl. In some embodiments, PEP1 is D-Lys, PEP2 is absent, and N- Terminus is acetyl. In some embodiments, PEP1 is D-Arg, PEP2 is absent, and N-Terminus is acetyl. In some embodiments, PEP1 is absent, PEP2 is D-Lys, and N-Terminus is acetyl. In some embodiments, PEP1 is absent, PEP2 is D-Arg, and N-Terminus is acetyl.

[0104] In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP2 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N- Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NEE. In some embodiments, LI, L2, L3, and L4 are each absent.

[0105] In some embodiments, PEP1 is a peptide sequence, and N-terminus is acyl. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length, and N-terminus is Ci- eacyl. In some embodiments, PEP1 is D-Lys, and N-terminus is Ci-eacyl. In some embodiments, PEP1 is D-Arg, and N-terminus is Ci-eacyl. In some embodiments, PEP1 is D-Arg-D-Arg, and N-terminus is Ci- eacyl. In some embodiments, PEP1 is absent, and N-terminus is Ci-eacyl. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys, and N-terminus is Ci-eacyl. In some embodiments, PEP2 is D-Arg, and N- terminus is Ci-eacyl.

[0106] In some embodiments, PEP1 is a peptide sequence, and N-terminus is acetyl. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length, and N-terminus is acetyl. In some embodiments, PEP1 is D-Lys, and N-terminus is acetyl. In some embodiments, PEP1 is D-Arg, and N-terminus is acetyl. In some embodiments, PEP1 is D-Arg-D-Arg, and N-terminus is acetyl. In some embodiments, PEP1 is absent, and N-terminus is acetyl. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. InWSGR Docket No. 65156-703.601 some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys, and N-terminus acetyl. In some embodiments, PEP2 is D-Arg, and N-terminus acetyl.

[0107] In some embodiments, each residue of the peptide nucleic acid sequence has a structure that is independently Y or x, wherein: each Y is independentlyeach x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3is H and each Ralrha2is hydroxyalkyl; or each R3is hydroxyalkyl and each RalPha2is H; or each R3and each RalPha2is H.

[0108] In some embodiments, each residue of the peptide nucleic acid sequence has a structure that is independently Y or x, wherein: each Y is independentlyeach x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPhalis H; or each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3and RalPha2is H.

[0109] In some embodiments, Z is -YYxxxYYxxxxYYxxxxYY-. In some embodiments, Z is - YYxxxxxYYxxxxYYxxxxYY-. In some embodiments, Z is -YYxxxxxYYxxxxxYYxxxxxYY-. In some embodiments, Z is -YxxxxxYYYxYYYxxxxxY-. In some embodiments, Z is -YxxxxxxYYYxYYYxxxxxxY-. In some embodiments, Z is -YxxxxxxxYYYxYYYxxxxxxxY-. In someWSGR Docket No. 65156-703.601 embodiments, Z is -YxYxxYxxYxYxxYxxY-. In some embodiments, Z is -YxYxxYxY xxY xY xYxY-. In some embodiments, Z is -YxYxYxY xYxYxYxYxY-. In some embodiments, Z is - YxxYxxYxxYxxYxxYxxY-. In some embodiments, Z is -YxYxYxxYxYxYxxYxYxY-. In some embodiments, Z is -YxxxYxxYxxxYxxYxxYxxY-. In some embodiments, Z is - YxYxxYxxYxxYxxYxxYxxY-. In some embodiments, Z is -YxYxxYxYxxYxxYxYxYxxY-. In some embodiments, Z is -YxxYxxxYxxxYxxYxxxYxxxY-. In some embodiments, Z is - YxxxYxxYxxYxxYxxYxxYxxY-. In some embodiments, Z is -YxYxxYxxYxxYxxYxxYxxYxY-. In some embodiments, Z is -YxxxYxxxYxxxYxxxYxxxYxxxY-. In some embodiments, Z is - YxxxYxxYxxxYxxYxxYxxYxxxY-. In some embodiments, Z is -YxxYxxYxxYxxYxxYxxYxxYxxY-.

[0110] In some embodiments, Z is (xY)yi, wherein yl is 5, 6, 7, 8, 9, or 10. In some embodiments, yl is 6. In some embodiments, yl is 7. In some embodiments, yl is 8. In some embodiments, Z is - YxYxYxYxYxYxYxYxY-. In some embodiments, Z is -YxYxYxYxYxYxY-. In some embodiments, Z is -YxYxYxYxYxYxYx-.

[0111] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-77. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-34. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-24. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-12 and 14-34. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-12 and 14-24. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 5-12 and 14-34. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 5-12 and 14-24. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-34, and PEP1 and PEP2 are each independently a peptide sequence. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-24, and PEP1 and PEP2 are each independently a peptide sequence. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-34, and PEP1 and PEP2 are each lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, and PEP1 and PEP2 are each D-lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-34, and PEP1 and PEP2 are each D-lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, and PEP1 and PEP2 are each D-lysine. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments,WSGR Docket No. 65156-703.601PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, PEP1 is absent, and N-Terminus is Ci-eacyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0112] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-77, and N-terminus is acyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-77, and N-terminus is Ci-eacyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-77, and N-terminus is acetyl. In some embodiments, each of PNA1 and PNA2 are absent.

[0113] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, and N-terminus is acyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, and N-terminus is Ci-eacyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, and N-terminus is acetyl. In some embodiments, each of PNA1 and PNA2 are absent.

[0114] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, PEP1 is absent, and N-terminus is acyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, PEP1 is absent, and N-terminus is Ci-eacyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-64, PEP1 is absent, and N-terminus is acetyl. In some embodiments, each of PNA1 and PNA2 are absent.

[0115] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 38, 47, 50, 58 59, 60, and 64, PEP1 is absent, and N-terminus is acyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 38, 47, 50, 58 59, 60, and 64, PEP1 is absent, and N-terminus is Ci-eacyl. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 38, 47, 50, 58 59, 60, and 64, PEP1 is absent, and N-terminus is acetyl. In some embodiments, each of PNA1 and PNA2 are absent.

[0116] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-12 and 14-29. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 5-12 and 14-29. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-29, and PEP1 and PEP2 are each independently a peptide sequence. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-29, and PEP1 and PEP2 are each lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-29, and PEP1 and PEP2 are each D-lysine. In some embodiments, each of PNA1 and PNA2 are absent.

[0117] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-12 and 14-24. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 5-12 and 14-24. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-24, and PEP1 and PEP2 are each independently a peptide sequence. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-24, and PEP1WSGR Docket No. 65156-703.601 and PEP2 are each lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-24, and PEP1 and PEP2 are each D-lysine. In some embodiments, each of PNA1 and PNA2 are absent.

[0118] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 25-29. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 25-29, and PEP1 and PEP2 are each independently a peptide sequence. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 25-29, and PEP1 and PEP2 are each lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 25-29, and PEP1 and PEP2 are each D-lysine. In some embodiments, each of PNA1 and PNA2 are absent.

[0119] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 30-34. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 30-34, and PEP1 and PEP2 are each independently a peptide sequence. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 30-34, and PEP1 and PEP2 are each lysine. In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 30-34, and PEP1 and PEP2 are each D-lysine. In some embodiments, each of PNA1 and PNA2 are absent.

[0120] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 65-70. In some embodiments, each of PNA1 and PNA2 are absent.

[0121] In some embodiments, Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 71-77. In some embodiments, each of PNA1 and PNA2 are absent.

[0122] In some embodiments, Z contains at least one cytosine-adenine-guanine sequence. In some embodiments, Z contains at least two cytosine-adenine-guanine sequences. In some embodiments, Z contains at least three cytosine-adenine-guanine sequences.

[0123] In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N- terminus of a contiguous adenine-containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C- terminus to an N-terminus of a contiguous guanine-containing peptide nucleic acid residue is an adenine- containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous cytosine-containing peptide nucleic acid residue is a guanine-containing peptide nucleic acid residue.

[0124] In some embodiments, Z contains at least one cytosine-thymine-guanine sequence. In some embodiments, Z contains at least two cytosine-thymine-guanine sequences. In some embodiments, Z contains at least three cytosine-thymine-guanine sequences.

[0125] In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N- terminus of a contiguous thymine-containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C- terminus to an N-terminus of a contiguous guanine-containing peptide nucleic acid residue is a thymine-WSGR Docket No. 65156-703.601 containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous cytosine-containing peptide nucleic acid residue is a guanine-containing peptide nucleic acid residue.

[0126] In some embodiments, PNA1 is the peptide nucleic acid sequence. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 200 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 100 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 50 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 25 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 15 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 5 residues in length. In some embodiments, PNA1 is absent.

[0127] In some embodiments, PNA2 is the peptide nucleic acid sequence. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 200 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 100 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 50 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 25 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 15 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 5 residues in length. In some embodiments, PNA2 is absent.

[0128] In some embodiments, PNA1 is -(Y)e(x)h-, wherein h is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and e is 1 or 2. In some embodiments, PNA1 is -YYxxxx-. In some embodiments, PNA1 is -(Y)e(x)h-, wherein h is 0, 1, 2, 3, 4, 5, 6, or 7, and e is 1 or 2. In some embodiments, PNA1 is -YYxxx-. In some embodiments, PNA1 is -YYxxxx-. In some embodiments, PNA1 is -YYxxxxx-. In some embodiments, PNA1 is - Yxxxxx-. In some embodiments, PNA1 is -Yxxxxxx-. In some embodiments, PNA1 is -Yxxxxxxx-. In some embodiments, PNA1 is -Yxx-.In some embodiments, PNA1 is -Yx-. In some embodiments, PNA1 is -Y-.

[0129] In some embodiments, PNA1 is -YWY-. In some embodiments, PNA1 is -YWYWWYWY-.

[0130] In some embodiments, PNA2 is -(x)g(Y) , wherein g is 3, 4, 5, 6, 7, 8, 9, or 10, and i is 1 or 2. In some embodiments, PNA2 is -xxxxYY-. In some embodiments, PNA2 is -(x)g(Y)i-, wherein g is 4, 5, 6, or 7, and i is 1 or 2. In some embodiments, PNA2 is -xxxYY-. In some embodiments, PNA2 is - xxxxYY-. In some embodiments, PNA2 is -xxxxxYY-. In some embodiments, PNA2 is -xxxxxY -. In some embodiments, PNA2 is -xxxxxxY-. In some embodiments, PNA2 is -xxxxxxxY-.

[0131] In some embodiments, PNA2 is -Y-. In some embodiments, PNA2 is -xxYxxxY-. In some embodiments, PNA2 is -YxxY-. In some embodiments, PNA2 is -xxYxYxYxxY-.

[0132] In some embodiments, PNA2 is -(xxY)„2- wherein n2 is 1, 2, 3, 4, or 5. In some embodiments, n2 is 2.WSGR Docket No. 65156-703.601

[0133] In some embodiments, PNA2 is -(Yx)niY-, wherein nl is 1, 2, 3, 4, or 5. In some embodiments, nl is 2. In some embodiments, nl is 3.

[0134] In some embodiments, PNA2 is -W-. In some embodiments, PNA2 is -WY-. In some embodiments, PNA2 is -YWYWYWWY-.

[0135] In some embodiments, -PNA1-Z-PNA2- is a contiguous peptide nucleic acid sequence that is from 10 to 250 residues in length. In some embodiments, -PNA1-Z-PNA2- is a contiguous peptide acid nucleic sequence that is from 10 to 200 residues in length. In some embodiments, -PNA1-Z-PNA2- is a contiguous peptide nucleic acid sequence that is from 10 to 100 residues in length. In some embodiments, -PNA1-Z-PNA2- is a contiguous peptide nucleic acid sequence that is from 10 to 50 residues in length. In some embodiments, -PNA1-Z-PNA2- is a contiguous peptide nucleic acid sequence that is from 10 to 30 residues in length. In some embodiments, -PNA1-Z-PNA2- is a contiguous peptide nucleic acid sequence that is from 15 to 30 residues in length.

[0136] In some embodiments, each R2is independently methyl substituted with a nucleobase. In some embodiments, each R4is independently methyl substituted with a nucleobase. In some embodiments, each RGis independently methyl substituted with a nucleobase. In some embodiments, each R2is independently methyl substituted with cytosine, adenine, or guanine. In some embodiments, each R2is independently methyl substituted with cytosine, thymine, or guanine. In some embodiments, each RGis independently methyl substituted with cytosine, thymine, or guanine. In some embodiments, each R4is independently methyl substituted with cytosine, adenine, or guanine. In some embodiments, each R4is independently methyl substituted with cytosine, thymine, or guanine. In some embodiments, each RGis independently methyl substituted with cytosine, thymine, or guanine.

[0137] In some embodiments, the present disclosure provides a compound of formula (VI), or a pharmaceutically-acceptable salt or ionized form thereof:us(VI)wherein: '-Tcrminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent;- Z is -(Ul)(X5)-xY-(X8)(X9)-YYx-(XI3)(XI4)(XI5)(XI6)-Y-(U2)-;- U1 is -Yx-(X3)(X4)-, -x-(X3)(X4)-, -(X3)(X4)-, -(X4)-, or absent;U2 is -x-(XI9)-, -x-, or absent;- each of X3, X4, X5, X8, X9, XI 2, XI 3, XI 4, XI 5, XI 6, and X19 is independently Y or x;WSGR Docket No. 65156-703.601 each Y is independentlyeach x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH.

[0138] In some embodiments, X3 is x. In some embodiments, X3 is Y. In some embodiments, X4 is x. In some embodiments, X4 is Y. In some embodiments, X5 is x. In some embodiments, X5 is Y. In some embodiments, X8 is x. In some embodiments, X8 is Y. In some embodiments, X9 is x. In some embodiments, X9 is Y. In some embodiments, X12 is x. In some embodiments, X12 is Y. In some embodiments, X13 is x. In some embodiments, X13 is Y. In some embodiments, X14 is x. In some embodiments, X14 is Y. In some embodiments, X15 is x. In some embodiments, X15 is Y. In some embodiments, X16 is x. In some embodiments, X16 is Y. In some embodiments, X19 is x. In some embodiments, X19 is Y.

[0139] In some embodiments, X9 and X15 are each x. In some embodiments, X9, X15, and X18 are each x.

[0140] In some embodiments, X8 and X13 are each Y. In some embodiments, X8, X13, and X16 are each Y.

[0141] In some embodiments, X4 is Y, and X8 is x. In some embodiments, X4 is Y, and X16 is x. In some embodiments, X4 is Y, and X8 and X16 are each x.

[0142] In some embodiments, X5 and X13 are each x, and X8 is Y. In some embodiments, X5, X13, and X16 are each x, and X8 is Y.

[0143] In some embodiments, X5 is Y, and X8 is x. In some embodiments, X5 is Y, and X13 is x. In some embodiments, X5 is Y, and X16 is x. In some embodiments, X5 is Y, and X8, X13, and X16 are each x.WSGR Docket No. 65156-703.601

[0144] In some embodiments, Z is -(Ul)YxYxYYYxYxYxY(U2)-. In some embodiments, Z is - YxYxYxYYYxYxY xY-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 71.

[0145] In some embodiments, Z is -(Ul)YxYYxYYxYYxYY(U2)-. In some embodiments, Z is - xYxYYxYYxYYxYYx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 72. In some embodiments, Z is -YxYYxYYxYYxYYxx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 73.

[0146] In some embodiments, Z is -(Ul)YxYxxYYxYYxxY(U2)-. In some embodiments, Z is - YxxYYxYxxYYxYYxxYx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 74. In some embodiments, Z is -xxYYxYxxYYxYYxxYxY-.

[0147] In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 75. In some embodiments, Z is -(Ul)xxYYxYYxxYxxY(U2)-. In some embodiments, Z is - YxxYYxYYxxY xxYx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 76.

[0148] In some embodiments, Z is -(Ul)YxYxxYYxxYxxY(U2)-. In some embodiments, Z is - YxYxxYYxxYxxYxY-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 77.

[0149] In some embodiments, each R2is independently methyl substituted with a nucleobase. In some embodiments, each R4is independently methyl substituted with a nucleobase. In some embodiments, each R2is independently methyl substituted with cytosine, adenine, or guanine. In some embodiments, each R2is independently methyl substituted with cytosine, thymine, or guanine. In some embodiments, each R4is independently methyl substituted with cytosine, adenine, or guanine. In some embodiments, each R4is independently methyl substituted with cytosine, thymine, or guanine.

[0150] In some embodiments, each R2is independently methyl substituted with a nucleobase selected from cytosine and thymine.

[0151] In some embodiments, the nucleobases of R2and R4together form at least one cytosine-thymine- guanine sequence. In some embodiments, the nucleobases of R2and R4together form at least two contiguous cytosine-thymine-guanine sequences. In some embodiments, the nucleobases of R2and R4together form at least three contiguous cytosine-thymine-guanine sequences. In some embodiments, the nucleobases of R2and R4together form at least four contiguous cytosine-thymine-guanine sequences. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous thymine-containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous guanine-containing peptide nucleic acid residue is a thymine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous cytosine-containing peptide nucleic acid residue is a guanine -containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its N-terminus to a C-terminus of a contiguous thymine-containing peptide nucleic acidWSGR Docket No. 65156-703.601 residue is a guanine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its N-terminus to a C-terminus of a contiguous guanine -containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its N-terminus to a C-terminus of a contiguous cytosine- containing peptide nucleic acid residue is a thymine -containing peptide nucleic acid residue.

[0152] In some embodiments, the nucleobases of R2and R4together form at least one cytosine-adenine- guanine sequence. In some embodiments, the nucleobases of R2and R4together form at least two contiguous adenine -thymine -guanine sequences. In some embodiments, the nucleobases of R2and R4together form at least three contiguous cytosine-adenine-guanine sequences. In some embodiments, the nucleobases of R2and R4together form at least four contiguous cytosine-adenine-guanine sequences. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous adenine-containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous guanine-containing peptide nucleic acid residue is an adenine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous cytosine-containing peptide nucleic acid residue is a guanine -containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its N-terminus to a C-terminus of a contiguous adenine-containing peptide nucleic acid residue is a guanine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its N-terminus to a C-terminus of a contiguous guanine -containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue. In some embodiments, each peptide nucleic acid residue that is bound via its N-terminus to a C-terminus of a contiguous cytosine- containing peptide nucleic acid residue is an adenine-containing peptide nucleic acid residue.

[0153] In some embodiments, PNA1 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, PNA1 is absent. In some embodiments, PNA2 is a peptide nucleic acid sequence that is from 1 to 10 residues in length. In some embodiments, PNA2 is absent. In some embodiments, PEP1 is a peptide sequence. In some embodiments, PEP1 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP1 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP1 is D-Lys. In some embodiments, PEP1 is D-Arg. In some embodiments, PEP1 is D-Arg -D-Arg. In some embodiments, PEP1 is absent. In some embodiments, PEP2 is a peptide sequence. In some embodiments, PEP2 is a peptide sequence that is from 1 to 5 residues in length. In some embodiments, PEP2 is a peptide sequence that is 1 or 2 residues in length. In some embodiments, PEP2 is D-Lys. In some embodiments, PEP2 is D-Arg. In some embodiments, PEP1 is D-Arg-D-Arg. In some embodiments, PEP2 is absent. In some embodiments, N-Terminus is acyl. In some embodiments, N-Terminus is acetyl. In some embodiments, N-Terminus is H. In some embodiments, C-Terminus is NH2. In some embodiments, LI, L2, L3, and L4 are each absent.

[0154] In some embodiments, each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPhalis H; or each R1is H and each RalPhalisWSGR Docket No. 65156-703.601 independently alkyl substituted with a group that bears a positive charge at physiological pH. In some embodiments, each R1is H and each Ralrhalis independently alkyl substituted with a group that bears a positive charge at physiological pH. In some embodiments, each R1is independently guanidinoalkyl, and each RalPhalis H; or each R1is H and each RalPhalis independently guanidinoalkyl. In some embodiments, each R1is H and each RalPhalis independently guanidinoalkyl. In some embodiments, each R1is independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl, and each RalPhalis H; or each R1is H and each RalPhalis independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl. In some embodiments, each R1is H and each RalPhalis independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl. In some embodiments, each R1is 4-guanidinobut-l-yl, and each RalPhalis H; or each R1is H and each RalPhalis 3- guanidinoprop-l-yl. In some embodiments, each R1is 4-guanidinobut-l-yl, and each RalPhalis H. In some embodiments, each R1is H and each RalPhalis 3-guanidinoprop-l-yl.

[0155] In some embodiments, the present disclosure provides a compound of formula (VII), or a pharmaceutically-acceptable salt or ionized form thereof:us(V[[)wherein:JV-Terminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent;Z is a peptide nucleic acid sequence, wherein each residue of Z independently has a structure according to x or Y, wherein: each Y is independentlyeach x is independentlyeach R2is independently methyl substituted with a nucleobase that is not guanine; each R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; andWSGR Docket No. 65156-703.601 each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH.

[0156] In some embodiments, each R2is independently methyl substituted with cytosine or thymine. In some embodiments, each R4is independently methyl substituted with a nucleobase. In some embodiments, each R4is independently methyl substituted with cytosine, adenine, or guanine. In some embodiments, each R4is independently methyl substituted with cytosine, thymine, or guanine.

[0157] In some embodiments, at least about 20% of the residues of Z have a structure according to Y. In some embodiments, at least about 30% of the residues of Z have a structure according to Y. In some embodiments, at least about 40% of the residues of Z have a structure according to Y. In some embodiments, from about 20% to about 80% of the residues of Z have a structure according to Y. In some embodiments, from about 30% to about 80% of the residues of Z have a structure according to Y. In some embodiments, from about 40% to about 60% of the residues of Z have a structure according to Y. In some embodiments, from about 40% to about 70% of the residues of Z have a structure according to Y. In some embodiments, from about 40% to about 80% of the residues of Z have a structure according to Y. In some embodiments, no more than about 60% of the residues of Z have a structure according to Y. In some embodiments, no more than about 70% of the residues of Z have a structure according to Y. In some embodiments, no more than about 80% of the residues of Z have a structure according to Y.

[0158] In some embodiments, Z is from 10 to 100 residues in length. In some embodiments, Z is from 10 to 50 residues in length. In some embodiments, Z is from 10 to 30 residues in length. In some embodiments, Z is from 12 to 25 residues in length. In some embodiments, Z is from 10 to 16 residues in length. In some embodiments, Z is from 10 to 15 residues in length. In some embodiments, Z is from 14 to 16 residues in length. In some embodiments, Z is from 10 to 15 residues in length. In some embodiments, Z is 14, 15, 16, 17, 18, 19, or 20 residues in length. In some embodiments, Z is 14 residues in length. In some embodiments, Z is 15 residues in length. In some embodiments, Z is 16 residues in length. In some embodiments, Z is 14, 15, 16, 17, 18, 19, or 20 residues in length. In some embodiments, about 40% to about 60% of the residues of Z have a structure according to Y.

[0159] In some embodiments, Z is from 12 to 25 residues in length, wherein from 5 to 10 of the residues of Z have a structure according to Y. In some embodiments, Z is from 12 to 25 residues in length, wherein 5, 6, 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, Z is from 12 to 25 residues in length, wherein 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, Z is from 10 to 20 residues in length, wherein 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, Z is from 10 to 16 residues in length, wherein 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, Z is from 10 to 15 residues in length, wherein 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, Z is from 14 to 16 residues in length, wherein 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, Z is from 14 to 16 residues in length, wherein about 40% to about 60% of theWSGR Docket No. 65156-703.601 residues of Z have a structure according to Y. In some embodiments, each of PNA1 and PNA2 are absent.

[0160] In some embodiments, 5, 6, 7, 8, 9, or 10 of the residues of Z have a structure according to Y. In some embodiments, 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, 7 of the residues of Z have a structure according to Y. In some embodiments, 8 of the residues of Z have a structure according to Y. In some embodiments, 9 of the residues of Z have a structure according to Y. In some embodiments, 7, 8, or 9 of the residues of Z have a structure according to Y. In some embodiments, 7 of the residues of Z have a structure according to Y. In some embodiments, 8 of the residues of Z have a structure according to Y. In some embodiments, 9 of the residues of Z have a structure according to Y.

[0161] In some embodiments, Z is -xYxYYxYYxYYxYYx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 72.

[0162] In some embodiments, Z is -YxYYxYYxYYxYYxx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 73.

[0163] In some embodiments, Z is -YxxYYxY xxYYxYYxxYx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 74.

[0164] In some embodiments, Z is -xxYYxYxxYYxYYxxYxY-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 75.

[0165] In some embodiments, Z is -YxxYYxYYxxYxxYx-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 76.

[0166] In some embodiments, Z is -YxY xxYYxxYxxYxY-. In some embodiments, Z is a peptide nucleic acid sequence according to SEQ ID NO 77.

[0167] In some embodiments, N-terminus is H. In some embodiments, N-terminus is acyl. In some embodiments, N-terminus is Ci-4acyl. In some embodiments, N-terminus is acetyl. In some embodiments, N-terminus is a fluorophore. In some embodiments, N-terminus is a biologically active compound. In some embodiments, the biologically active compound is therapeutically-active. In some embodiments, the biologically active compound is diagnostically active. In some embodiments, the biologically active compound is an oligonucleotide or a targeted small molecule inhibitor or activator.

[0168] In some embodiments, C-terminus is -O-alkyl. In some embodiments, C-terminus is O-Ci-ealkyl. In some embodiments, C-terminus is -OMe. In some embodiments, C-terminus is -OEt. In some embodiments, C-terminus is -NH2. In some embodiments, C-terminus is a fluorophore. In some embodiments, C-terminus is a biologically active compound. In some embodiments, the biologically active compound is therapeutically-active. In some embodiments, the biologically active compound is diagnostically active. In some embodiments, the biologically active compound is an oligonucleotide or a targeted small molecule inhibitor or activator.

[0169] In some embodiments, each of LI, L2, L3, and L4 is independently absent or a linker group. In some embodiments, each of LI and L4 is independently the linker group. In some embodiments, each of L2 and L3 is independently the linker group. In some embodiments, LI is the linker group. In someWSGR Docket No. 65156-703.601 embodiments, L2 is the linker group. In some embodiments, L3 is the linker group. In some embodiments, L4 is the linker group. In some embodiments, the linker group is cleavable. In some embodiments, the linker group is non-cleavable. In some embodiments, the linker group is a peptide sequence. In some embodiments, the linker group is a polyamine sequence. In some embodiments, the linker group is a polyamide sequence. In some embodiments, the linker group comprises polyethylene glycol. In some embodiments, the linker is cleavable by physiological conditions. In some embodiments, each of LI, L2, L3, and L4 is absent.

[0170] In some embodiments, LI is the linker group. In some embodiments, the linker group is cleavable. In some embodiments, the linkergroup is non-cleavable. In some embodiments, the linker group is a peptide sequence. In some embodiments, the linker group is a polyamine sequence. In some embodiments, the linker group is a polyamide sequence. In some embodiments, the linker group comprises polyethylene glycol. In some embodiments, the linker is cleavable by physiological conditions. In some embodiments, the linker is not cleavable by physiological conditions. In some embodiments, LI is absent.

[0171] In some embodiments, L2 is the linker group. In some embodiments, the linker group is cleavable. In some embodiments, the linkergroup is non-cleavable. In some embodiments, the linker group is a peptide sequence. In some embodiments, the linker group is a polyamine sequence. In some embodiments, the linker group is a polyamide sequence. In some embodiments, the linker group comprises polyethylene glycol. In some embodiments, the linker is cleavable by physiological conditions. In some embodiments, the linker is not cleavable by physiological conditions. In some embodiments, L2 is absent.

[0172] In some embodiments, L3 is the linker group. In some embodiments, the linker group is cleavable. In some embodiments, the linkergroup is non-cleavable. In some embodiments, the linker group is a peptide sequence. In some embodiments, the linker group is a polyamine sequence. In some embodiments, the linker group is a polyamide sequence. In some embodiments, the linker group comprises polyethylene glycol. In some embodiments, the linker is cleavable by physiological conditions. In some embodiments, the linker is not cleavable by physiological conditions. In some embodiments, L3 is absent.

[0173] In some embodiments, L4 is the linker group. In some embodiments, the linker group is cleavable. In some embodiments, the linkergroup is non-cleavable. In some embodiments, the linker group is a peptide sequence. In some embodiments, the linker group is a polyamine sequence. In some embodiments, the linker group is a polyamide sequence. In some embodiments, the linker group comprises polyethylene glycol. In some embodiments, the linker is cleavable by physiological conditions. In some embodiments, the linker is not cleavable by physiological conditions. In some embodiments, L4 is absent.

[0174] In some embodiments, each of R2and R4is independently methyl substituted with a nucleobase.WSGR Docket No. 65156-703.601

[0175] In some embodiments, each nucleobase together forms a sequence of nucleobases that binds a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0176] In some embodiments, each nucleobase together forms a sequence of nucleobases that is complementary to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0177] In some embodiments, each nucleobase together forms a sequence of nucleobases that is complementary to a target sequence within a trinucleotide repeat expansion, wherein the trinucleotide repeat expansion is causative of a repeat expansion disease.

[0178] A peptide nucleic acid sequence herein can comprise at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100% sequence complementarity to a target region within the target nucleic acid sequence to which the peptide nucleic acid sequence is targeted. For example, a peptide nucleic acid in which 18 of 20 nucleotides of the antisense compound are complementary to a target region within a target nucleic acid, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleotides may be clustered or interspersed with complementary nucleotides and need not be contiguous to each other or to complementary nucleotides. Percent complementarity between particular stretches of nucleic acid sequences within nucleic acids can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656) or by using the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489).

[0179] In some embodiments, each nucleobase together forms a sequence of nucleobases that has at least 80% complementarity to a target sequence of equal length within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease. In some embodiments, the sequence of nucleobases has at least 85% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 87% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 90% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 91% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 92% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 93% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 94% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 95% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 96% complementarity to the target sequence. In some embodiments, the sequence of nucleobases has at least 97% complementarity to the target sequence.WSGR Docket No. 65156-703.601

[0180] In some embodiments, each nucleobase together forms a sequence of nucleobases that has at least 80% identity to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0181] In some embodiments, target sequence consists of contiguous repeats of CAG, CGG, CTG, CUG, GAA, GAA, GCC, GCG, CCTG, CCUG, ATTCT, AUUCU, TGGAA, UGGAA, GGCCTG, GGCCUG, GGGGCC, or CCCCGCCCCGCG. In some embodiments, target sequence consists of contiguous repeats of CAG. In some embodiments, target sequence consists of contiguous repeats of CTG. In some embodiments, target sequence consists of contiguous repeats of CUG.

[0182] In some embodiments, target sequence consists of contiguous repeats of CAG, CGG, CCG, CTG, CUG, GAA, GGC, CGC, GCC, TTC, UUC, GCG, CCTG, CCUG, ATTCT, CAGG, AGAAT, AGAAU, TTCCA, UUCCA, AUUCU, TGGAA, UGGAA, GGCCTG, GGCCUG, GGGGCC, CAGGCC, GGCCCC, CCCCGCCCCGCG or CGCGGGGCGGGG. In some embodiments, target sequence consists of contiguous repeats of CAG. In some embodiments, target sequence consists of contiguous repeats of CTG. In some embodiments, target sequence consists of contiguous repeats of CUG.

[0183] In some embodiments, target sequence comprises contiguous repeats of CAG. In some embodiments, target sequence comprises contiguous repeats of CUG. In some embodiments, target sequence comprises contiguous repeats of CTG.

[0184] A polynucleotide (e.g., peptide nucleic acid) or polypeptide has a certain percent “sequence identity” to another polynucleotide or polypeptide, meaning that, when aligned, that percentage of bases or amino acids are the same, and in the same relative position, when comparing the two sequences. Sequence identity can be determined in a number of different manners. To determine sequence identity, sequences can be aligned using various methods and computer programs (e.g., BUAST, T-COFFEE, MUSCLE, MAFFT, etc.), available over the world wide web at sites including ncbi.nlm.nili.gov / BLAST, ebi.ac.uk / Tools / msa / tcoffee / , ebi.ac.uk / Tools / msa / muscle / , mafft.cbrc.jp / alignment / software / . See, e.g., Altschul et al. (1990), J. Mol. Bioi. 215:403-10.

[0185] In some embodiments, each nucleobase together forms a sequence of nucleobases that has at least 80% sequence identity to a complementary sequence of equal length, wherein the complementary sequence is complementary to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease. In some embodiments, the sequence of nucleobases has at least 85% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 87% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 90% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 91% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 92% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 93% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 94% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 95% sequence identity to the complementary sequence. In someWSGR Docket No. 65156-703.601 embodiments, the sequence of nucleobases has at least 96% sequence identity to the complementary sequence. In some embodiments, the sequence of nucleobases has at least 97% sequence identity to the complementary sequence.

[0186] In some embodiments, the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CAG, CGG, CTG, CUG, GAA, GAA, GCC, GCG, CCTG, CCUG, ATTCT, AUUCU, TGGAA, UGGAA, GGCCTG, GGCCUG, GGGGCC, or CCCCGCCCCGCG. In so me embodiments, the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CAG. In some embodiments, the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CTG. In some embodiments, the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CUG.

[0187] In some embodiments, the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CAG, CGG, CCG, CTG, CUG, GAA, GGC, CGC, GCC, TTC, UUC, GCG, CCTG, CCUG, ATTCT, CAGG, AGAAT, AGAAU, TTCCA, UUCCA, AUUCU, TGGAA, UGGAA, GGCCTG, GGCCUG, GGGGCC, CAGGCC, GGCCCC, CCCCGCCCCGCG, or CGCGGGG CGGGG.

[0188] In some embodiments, the expanded repeat region consists of contiguous repeats of CAG, CGG, CTG, CUG, GAA, GAA, GCC, GCG, CCTG, CCUG, ATTCT, AUUCU, TGGAA, UGGAA, GGCCTG, GGCCUG, GGGGCC, or CCCCGCCCCGCG. In some embodiments, the expanded repeat region consists of contiguous repeats of CAG. In some embodiments, the expanded repeat region consists of contiguous repeats of CTG. In some embodiments, the expanded repeat region consists of contiguous repeats of CUG.

[0189] In some embodiments, the expanded repeat region consists of contiguous repeats of CAG, CGG, CCG, CTG, CUG, GAA, GGC, CGC, GCC, TTC, UUC, GCG, CCTG, CCUG, ATTCT, CAGG, AGAAT, AGAAU, TTCCA, UUCCA, AUUCU, TGGAA, UGGAA, GGCCTG, GGCCUG, GGGGCC, CAGGCC, GGCCCC, CCCCGCCCCGCG, or CGCGGGGCGGGG.

[0190] In some embodiments, the expanded repeat region consists of (CAG)d, wherein d is at least 19, at least 20, at least 28, at least 35, at least 36, at least 37, at least 38, at least 40, at least 41, at least 44, at least 50, at least 53, at least 60, at least 70, at least 76, at least 80, at least 90, at least 100, at least 150, or at least 200. In some embodiments, d is at least 19. In some embodiments, d is at least 20. In some embodiments, d is at least 28. In some embodiments, d is at least 35. In some embodiments, d is at least 36. In some embodiments, d is at least 37. In some embodiments, d is at least 38. In some embodiments, d is at least 40. In some embodiments, d is at least 41. In some embodiments, d is at least 44. In some embodiments, d is at least 50. In some embodiments, d is at least 53. In some embodiments, d is at least 60. In some embodiments, d is at least 70. In some embodiments, d is at least 76. In some embodiments, d is at least 80. In some embodiments, d is at least 90. In some embodiments, d is at least 100. In some embodiments, d is at least 150. In some embodiments, d is at least 200. In some embodiments, d is no more than 60. In some embodiments, d is no more than 70. In some embodiments, d is no more than 76.WSGR Docket No. 65156-703.601In some embodiments, d is no more than 80. In some embodiments, d is no more than 90. In some embodiments, d is no more than 100. In some embodiments, d is no more than 125. In some embodiments, d is no more than 150. In some embodiments, d is no more than 151. In some embodiments, d is no more than 200. In some embodiments, d is from 15 to 100. In some embodiments, d is from 15 to 200. In some embodiments, d is from 15 to 500. In some embodiments, d is from 15 to 1000. In some embodiments, d is from 15 to 2000. In some embodiments, d is from 35 to 100. In some embodiments, d is from 35 to 200. In some embodiments, d is from 35 to 500.

[0191] In some embodiments, the expanded repeat region consists of (CAG)d, wherein d is from 35 to 1000. In some embodiments, d is from 35 to 2000. In some embodiments, d is from 27 to 36, from 27 to 36, from 27 to 40, from 27 to 60, from 27 to 80, from 27 to 90, from 36 to 40, from 36 to 60, from 36 to 80, from 36 to 90, from 40 to 60, from 40 to 80, from 40 to 90, or from 60 to 90.

[0192] In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is at least 50, at least 100, at least 200, at least 500, at least 800, or at least 1000. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is at least 50. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is at least 800. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is at least 1000. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is from 50 to 1000. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is from 1000 to 2000. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 2000. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 1000. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 800. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 500. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 250. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 150. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 100. In some embodiments, the expanded repeat region consists of (CTG)d, wherein d is no more than 50.

[0193] In some embodiments, the expanded repeat region consists of (CGG)d, wherein d is at least 55, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, or at least 200. In some embodiments, the repeat expansion consists of (CGG)d, wherein d is at least 55. In some embodiments, the expanded repeat region consists of (CGG)d, wherein d is at least 200. In some embodiments, the expanded repeat region consists of (CGG)d, wherein d is from 55-200. In some embodiments, the expanded repeat region consists of (CGG)d, wherein d is from 55-2000.

[0194] In some embodiments, the expanded repeat region is DNA. In some embodiments, the expanded repeat region is RNA. In some embodiments, the target sequence is DNA. In some embodiments, the target sequence is RNA.

[0195] In some embodiments, the expanded repeat region is causative of a repeat expansion disease. In some embodiments, the repeat expansion disease is a polyglutamine disease, Fragile X-associated ataxia syndrome, fragile X syndrome, myotonic dystrophy type 1, Huntington disease-like 2, spinocerebellarWSGR Docket No. 65156-703.601 ataxia type 8, Fuchs comeal dystrophy, Friedreich ataxia, Fragile XE syndrome, FRA16A (CGG)n repeat expansion, oculopharyngeal muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, spinocerebellar ataxia type 10, spinocerebellar ataxia type 31, spinocerebellar ataxia type 36, C9ORF72 frontotemporal dementia, or progressive myoclonic epilepsy type 1. In some embodiments, the repeat expansion disease is myotonic dystrophy type 1.

[0196] In some embodiments, the expanded repeat region is causative of a polyglutamine disease. In some embodiments, the polyglutamine disease is Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, or spinocerebellar ataxia type 17. In some embodiments, the polyglutamine disease is Huntington’s disease.

[0197] Non-limiting examples of compounds of the disclosure are provided in TABLE 1. Residue structures, pendant nucleobase identities, and monomer chemical names associated with the symbols used in the structure codes of TABLE 1 are provided in TABLE 2. Compounds can be provided as a pharmaceutically-acceptable salt, tautomer, or ionized form thereof.TABLE 1WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601aUnless otherwise noted, all C-termini are amidated.bPortion of structure code within braces (e.g., “{CpTnGnCpTpGnCpTpGnCnTpGnCnTpGn}”), when present, correspond to SEQ ID NOs provided in this column.TABLE 2WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601WSGR Docket No. 65156-703.601'Protcinogcnic amino acid residues in compounds provided in TABLE 1 are represented by the following one-letter codes: A: Z -alanine, R: Z -arginine, N: Z-asparaginc. D: Z-aspartic acid, C: Z-cysteine, E: Z- glutamic acid, Q: Z-glutamine, G: glycine, H: Z-histidine, I: Z-isoleucine, L: Z-leucine , K: Z-lysine, M: Z-methionine, F: Z-phenylalanine, P: Z-proline, S: Z-serine, T: Z-threonine, W: Z-tryptophan, Y: Z- tyrosine, V: Z-valine.bFor each residue, a chemical name is provided for the corresponding unincorporated monomer.cAn antipode of an Z-amino acid or chiral residue provided in this table is represented in TABLE 1 by the code of the chiral residue followed by an asterisk (*). For example, K* represents ZMysine.

[0198] In some embodiments, the present disclosure provides a compound, or a pharmaceutically - acceptable salt or ionized form thereof, wherein the compound has a structure according to a structure code provided in TABLE 1.

[0199] FIG. 1 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e.g. natural, modified, or non-natural nucleobases), or hydrogen. One or more oligonucleotide residues of a compound of the disclosure may be independently replaced with a residue comprising an alternative oligonucleotide backbone bearing an identical nucleobase. Nonlimiting examples of oligonucleotide backbones suitable for use in the present disclosure include phosphorothioate deoxyribonucleic acid (PS- DNA), boranophosphate DNA, alpha-, beta-constrained nucleic acid (a,[3-CnA), 2'-methoxyribonucleic acid (2'-0Me-RNA), 2'-fluororibonucleic acid (2'-F-RNA), 2'-fhroroarabinonucleic acid (2'-F-ANA),WSGR Docket No. 65156-703.601 sulfonyl-linked nucleic acid, methylene(methylimino) (MMI) linked, formacetal-linked nucleic acid, threose nucleic acid (TNA), 2'-methoxyribonucleic acid (2'-0Me-RNA), 2'-O-(2- methoxyethyl)ribonucleic acid (2'-M0E-RNA), unlocked nucleic acid (UNA), 2'-O,4'-C-ethylene- bridged nucleic acid (ENA), 2'-O,4'-C-propylene bridged nucleic acid (PrNA), bridged nucleic acids (e.g., 2',4'-BNAC0C, 2',4'-BNANC[NH], 2',4'-BNANC[NMe], 3',4'-BNA), locked nucleic acid (LNA), bicylco[3.2.1]nucleic acid, (.S') -constrained ethyl nucleic acid ((S)-cEt), hexitol nucleic acid (HNA), homo-deoxyribonucleic acid (hNDA), phosphorodiamidate morpholino oligomer (PMO), peptide nucleic acid (PNA), cyclohexene nucleic acid (CeNA), benzene phosphate backbone, tricyclo-DNA(tcDNA), glycol nucleic acid (GNA), and epimers and diastereomers thereof.

[0200] In some embodiments, sequence variants of the sequences described herein are contemplated. A variant typically differs from a sequence specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of sequences of the disclosure and evaluating one or more biological activities of the compounds as described herein. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid and / or nucleic acid sequences of the compound. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., modulation of a genetic target.

[0201] Compounds disclosed herein can additionally comprise non-proteogenic acids in place of one or more proteogenic amino acids amino acids. Such non-proteogenic acids can include, for example, [3- alanine, cystine, cystathionine, lanthionine, t-leucine, norleucine, homonorleucine, ornithine, allothreonine, homocysteine, citrulline, homoserine, isovaline, norvaline, sarcosine, N-ethyl glycine, N- propyl glycine, N-isopropyl glycine, N-methyl alanine, N-ethyl alanine, N-methyl [3-alanine, N-ethyl [3- alanine, and isoserine.

[0202] Compounds described herein can be associated with modifications of one or more amino acids of the compounds. Non-limiting examples of modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N-linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitination, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, famesylation, geranylation, glypiation, lipoylation and iodination.

[0203] The nucleobases within a PNA subunit can be naturally occurring or non-naturally occurring. Non-limiting examples of nucleobases include adenine, guanine, thymine, cytosine, uracil, pseudoisocytosine, 2-thiopseudoisocytosine, 5-methylcytosine, 5 -hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine (or 2,6-diaminopurine), 2-thiouracil, 2-thiothymine, 2-thiocytosine, 5- chlorouracil, 5 -bromouracil, 5-iodouracil, 5 -chlorocytosine, 5 -bromocytosine, 5 -iodocytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 7-methylguanine, 7- methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3 -deazaguanine, 3- deazaadenine, 7-deaza-8-aza guanine, 7-deaza-8-aza adenine, 5-propynyl uracil and 2-thio-5-propynyl,WSGR Docket No. 65156-703.601 pyridazin-3(2H)-one (E), pyrimidin-2(lH)-one (P) and 2-aminopyridine (M), and tautomeric forms thereof. In some embodiments, a naturally occurring nucleobase of a compound provided herein is replaced with a non-naturally occurring analogue. An adenine nucleobase of a compound herein can be replaced with, for example, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, or 3- deazaadenine.

[0204] Compounds described herein (e.g., PNA subunits and PNA oligomers) can comprise one or more isotopic substitutions. For example, hydrogen can be in any isotopic form, including ’H (protium),2H (D or deuterium), and3H (T or tritium). Carbon can be in any isotopic form, including12C,13C, and14C. Oxygen can be in any isotopic form, including16O and18O.

[0205] Compounds described herein (e.g., PNA subunits and PNA oligomers) can comprise one or more asymmetric centers, and can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods including chiral high-performance liquid chromatography (HPLC), selective crystallization as chiral salts, or in the presence of chiral hosts, or from chiral solvents, and through enrichment using enzymes or chemical processes such as dynamic kinetic resolution. A single isomer can be prepared by asymmetric synthesis. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0206] Polypeptides and proteins disclosed herein (including functional portions and functional variants thereof) can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids can include, for example, aminocyclohexane carboxylic acid, norleucine, a- amino n-decanoic acid, homoserine, S-acetylaminomethyl-cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, [3- phenylserine [3-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N’ -benzyl -N’ -methyl -lysine, N’,N’-dibenzyl-lysine, 6-hydroxylysine, ornithine, a-aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a-aminocycloheptane carboxylic acid, a-(2-amino-2-norbomane)-carboxylic acid, a,y-diaminobutyric acid, a,P-diaminopropionic acid, homophenylalanine, and a-tert-butylglycine.

[0207] In some embodiments, a compound of a disclosure is substituted with one or more nitrogen protecting groups. Nonlimiting examples of nitrogen protecting groups include methyl, formyl, ethyl, acetyl, anisyl, benzyl, benzoyl, carbamate, trifluoroacetyl, diphenylmethyl, triphenylmethyl, benzyloxymethyl, benzyloxycarbonyl, 2-nitrobenzoyl, t-Boc (tert-butyloxycarbonyl), 4-methylbenzyl, 4- nitrophenyl, 2-chlorobenzyloxycarbonyl, 2- bromobenzyloxycarbonyl, 2,4,5-trichlorophenyl, thioanizyl, thiocresyl, cbz (carbobenzyloxy), p-methoxybenzyl carbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), pentafluorophenyl, p-methoxybenzyl, 3,4-dimethozybenzyl, p-methoxyphenyl, 4-toluenesulfonyl, p- nitrobenzenesulfonates, 9-fluorenylmethyloxycarbonyl, 2-nitrophenylsulfenyl, 2,2,5,7,8-pentamethyl-WSGR Docket No. 65156-703.601 chroman-6-sulfonyl, 2-(4-Nitrophenyl)sulfonylethoxycarbonyl (Nsc), l,l-Dioxobenzo[b]thiophene-2- ylmethyloxycarbonyl (Bsmoc), l,l-Dioxonaphtho[l,2-b]thiophene-2 -methyloxycarbonyl (a-Nsmoc), 3, 3-Dioxonaphtho[2, l-b]thiophene-2 -methyloxycarbonyl ([3-Nsmoc), l-(4,4-dimethyl-2,6- dioxocyclohex- 1 -ylidene)-3 -methylbutyl (ivDde), 2, 7-di - / c77-biity I -9-fl uorcny I methoxy carbonyl (Fmoc*), 2-monoisooctyl-9-fluorenylmethoxycarbonyl (mio-Fmoc), 2,7-diisooctyl-9- fluorenylmethoxycarbonyl, tetrachlorophthaloyl (TCP), 2-fluoro-9-fluorenylmethoxycarbonyl (Fmoc(2F)), 2-[Phenyl(methyl)sulfonio]ethyloxycarbonyl tetrafluoroborate (Pms), ethane sulfonylethoxy carbonyl (Esc), 2-(4-sulfophenylsulfonyl)ethoxycarbonyl (Sps), N,N- dimethylaminoxycarbonyl (Dmaoc), and p-bromobenzenesulfonyl.Chemical Groups.

[0208] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, hydrocarbyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.

[0209] Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups. An alkyl group can be, for example, a Ci, C2, C3, C4, C5, Ce, C7, Cs, C>, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, C20, C2I, C22, C23, C24, C25, C26, C27, C28, C29, C30, C3I, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. In some embodiments, each alkyl is independently a Ci-ioalkyl. In some embodiments, each alkyl is independently a Ci-iealkyl. In some embodiments, each alkyl is independently a Ci-4alkyl.

[0210] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0211] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t- butyl.

[0212] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.

[0213] Non-limiting examples of alkenyl or alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C2I, C22, C23, C24, C25, C26, C27, C28, C29, C30, C3I, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. In some embodiments, each alkenyl is independently a Ci-ioalkenyl.WSGR Docket No. 65156-703.601

[0214] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkynyl or alkynylene group can be internal or terminal. An alkynyl or alkynylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, Cw, Cn, C12, C13, C14, C15, Ci6, C17, C18, C19, C20, C2I, C22, C23, C24, C25, C26, C27, C28, C29, C30, Csi, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted.

[0215] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms. In some embodiments, each haloalkyl is independently a Ci-iohaloalkyl. In some embodiments, each haloalkyl is independently a Ci-iehaloalkyl. In some embodiments, each haloalkyl is independently a Ci-4halolkyl.

[0216] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. In some embodiments, each alkoxy group is independently a Ci-ealkoxy. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0217] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. In some embodiments, each aryl is independently a C4-ioaryl.

[0218] An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy. In some embodiments, each aryloxy is independently a C4-ioaryloxy.

[0219] An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.

[0220] An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy. In some embodiments, each arylalkoxy is independently a C5-2oarylalkoxy. In some embodiments, each arylalkoxy is independently a Cs-ioarylalkoxy.

[0221] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include nucleobases, pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran. In some embodiments, each heterocycle is independently a 3- to 12-membered monocyclic, bicyclic, or tricyclic ring containing 1 to 10 N, O, S, P, Si, or B atoms. In some embodiments, each heterocycle is a C2-10 heterocycle. In some embodiments, each heterocycle is a nitrogen-containing C2-10 heterocycle. In some embodiments, each heterocycle is a C2- 10 heterocycle optionally substituted with one or more of amino, hydroxy, oxo, C1.4 alkoxy, Ci-s alkyl, and C1-4WSGR Docket No. 65156-703.601 aminoalkyl. In some embodiments, each heterocycle is a nucleobase optionally substituted with a nitrogen protecting group.

[0222] An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxy carbonyl. In some embodiments, each acyl is independently a C2-2oacyl. In some embodiments, each acyl is independently a C2-ioacyl. In some embodiments, each acyl is independently a C2-4acyl.

[0223] An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or an ester group comprises an acyloxy group. A non-limiting example of an acyloxy group, or an ester group, is acetate.

[0224] A carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle.

[0225] A hydrocarbyl group can be any group consisting of carbon and hydrogen atoms, and can include alkyl groups, alkenyl groups, alkynyl groups, and aryl groups. A hydrocarbyl group can be, for example, a C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Ci s, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group.

[0226] A hydrocarbylcarbonyl group can be a carbonyl group substituted with a hydrocarbyl group, which can be, for example, benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undencanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, as well as acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, elaidoyl, vaccenoyl, linoleoyl, linoelaidoyl, a-linolenoyl, or arachidonoyl. A hydrocarylcarbonyl group can be, for example, a C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn , C12, C13, C14, C15, C16, C17, C18, C19, C20, C2I, C22, C23, C24, C25, C26, C27, C28, C29, C30, C3I, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group.

[0227] An aminoalkyl group can be an alkyl group substituted with an amino group, such as, for example, aminomethyl, 2-aminoeth-l-yl, 3 -aminoprop- 1-yl, 2-aminoprop-l-yl, 4-aminobut-l-yl, 3- aminobut-l-yl, 2-aminobut-l-yl, 5 -aminopent- 1-yl, 4-aminopent-l-yl, 4-aminopent-l-yl, 3 -aminopent- 1- yl, 2-aminopent-l-yl, a lysine side chain, or an ornithine side chain. In some embodiments, each aminoalkyl is a C1-10 independently aminoalkyl. In some embodiments, each aminoalkyl is independently a C1-6 aminoalkyl.

[0228] A guanidinoalkyl group can be an alkyl group substituted with a guanidino group, such as, for example, guanidinomethyl, 2-guanidinoeth-l-yl, 3-guanidinoprop-l-yl, 2-guanidinoprop-l-yl, 4- guanidinobut-l-yl, 3-guanidinobut-l-yl, 2-guanidinobut-l-yl, 5-guanidinopenty-l-l, 4-guanidinopent-l- yl, 4-guanidinopent-l-yl, 3-guanidinopent-l-yl, 2-guanidinopent-l-yl, an arginine side chain, or aWSGR Docket No. 65156-703.601 homoarginine side chain. In some embodiments, each guanidinoalkyl is independently a Cn 4guanidinoalkyl.Pharmaceutically-Acceptable Salts of Compounds Herein.

[0229] The disclosure provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and baseaddition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt.

[0230] Metal salts can arise from the addition of an inorganic base to a compound of the disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0231] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0232] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, A'-mcthylmorpholinc. piperidine, N- methylpiperidine, A-ethy Ipiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.

[0233] In some embodiments, an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an '-mcthy Imorphol inc salt, a piperidine salt, an '-mcth Ipiperidine salt, an '-cth Ipiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.

[0234] Acid addition salts can arise from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.WSGR Docket No. 65156-703.601

[0235] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a trifluoroacetate salt, a mandelate salt, a cinnamate salt, an aspartate salt, a stearate salt, a palmitate salt, a glycolate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzene sulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. In some embodiments, a compound herein is provided as a chloride salt. In some embodiments, a compound herein is provided as a trifluoroacetate salt. In some embodiments, a compound herein is provided as an acetate salt. In some embodiments, the acetate salt comprises about 10% (w / w) acetate.

[0236] A pharmaceutically acceptable salt of a compound herein can be prepared by a counterion exchange process. The counterion exchange process can be mediated by a strong anion exchange resin. The counterion exchange process can involve exposure of the compound to the strong anion exchange resin in the presence of excess acid of the desired salt form.

[0237] A compound herein can comprise one or more ionizable sites, such as, for example, one or more amine moieties. In cases where a compound herein is provided as a pharmaceutically-acceptable salt, the pharmaceutically-acceptable salt can comprise one or more counterions. In some embodiments, the pharmaceutically-acceptable salt comprises a plurality of counterions. In some embodiments, the pharmaceutically-acceptable salt comprises a plurality of counterions, wherein the plurality of counterions is two counterions, three counterions, four counterions, five counterions, six counterions, seven counterions, eight counterions, nine counterions, ten counterions, eleven counterions, twelve counterions, thirteen counterions, fourteen counterion, fifteen counterions, sixteen counterions, seventeen counterions, eighteen counterions, nineteen counterions, or twenty counterions. In some embodiments, the pharmaceutically-acceptable salt comprises a plurality of counterions, wherein the plurality of counterions is two to twenty counterions. In some embodiments, at least one counterion of the plurality of counterions is independently selected from fluoride, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, phosphate, nitrate, thiocyanate, and perchlorate. In some embodiments, at least one counterion of the plurality of counterions is independently selected from chloride, acetate, trifluoroacetate, and pamoate.

[0238] An amount of counterion in a pharmaceutically-acceptable salt of a compound herein can be articulated in terms of a percent of compound mass that is counterion. In some embodiments, a pharmaceutically-acceptable salt of a compound herein, or an ionized form thereof, comprises about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10% (w / w) counterion. In some embodiments, a pharmaceutically-acceptable salt of a compound herein, or an ionized form thereof, comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, aboutWSGR Docket No. 65156-703.60115%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30% (w / w) counterion. In some embodiments, the counterion is acetate. In some embodiments, the counterion is trifluoroacetate.

[0239] In some embodiments, a pharmaceutically-acceptable salt of a compound herein, or an ionized form thereof, comprises about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10% (w / w) acetate. In some embodiments, a pharmaceutically- acceptable salt of a compound herein, or an ionized form thereof, comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30% (w / w) acetate.Pharmaceutical compositions.

[0240] The present disclosure provides pharmaceutical compositions comprising a compound herein. A pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.

[0241] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.

[0242] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered orally. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by an intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intracerebroventricular, intra-articular, intraperitoneal, intracranial, intrathecal, intranasal, buccal, sublingual, oral, or rectal administration route. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intravenous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by subcutaneous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intracerebroventricular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided hereinWSGR Docket No. 65156-703.601(e.g., a pharmaceutical composition) is administered by oral administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intrathecal administration.

[0243] A pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended-release formulation can provide a controlled release or a sustained delayed release.

[0244] For oral administration, pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject. Nonlimiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2 -hydroxyethyl- 1 -piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2- ethane sulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.

[0245] Pharmaceutical preparations can be formulated for intravenous administration. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0246] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.The compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject. The compounds of the disclosure can be applied to an accessible body cavity.

[0247] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventionalWSGR Docket No. 65156-703.601 suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, and PEG. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.

[0248] In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0249] Pharmaceutical compositions can be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.

[0250] The pharmaceutical compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form. Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0251] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Solid composition can include lyophilized formulations. Semi-solid compositions include, for example, gels, suspensions, and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additive s .

[0252] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.

[0253] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.WSGR Docket No. 65156-703.601

[0254] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gelforming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0255] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.

[0256] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.

[0257] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0258] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The agents can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.

[0259] Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary. For example, the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition. The compositions can be administered to a subject during or asWSGR Docket No. 65156-703.601 soon as possible after the onset of the symptoms. The administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein.

[0260] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary for each subject.

[0261] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non- reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative. Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi dose containers with a preservative.

[0262] Pharmaceutical compositions provided herein, can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.

[0263] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage. For solid compositions, nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.WSGR Docket No. 65156-703.601

[0264] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics / antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.

[0265] Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect.Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.

[0266] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, antiadherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.

[0267] Compositions of the disclosure can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration / use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. The written material can be a label. In some embodiments, the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.

[0268] Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14%WSGR Docket No. 65156-703.601 pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

[0269] Pharmaceutical compositions and formulations described herein can comprise, for example, a compound provided herein at any suitable concentration. A formulation can comprise a composition provided herein at a concentration of, for example, about 0.001 mg / mL, about 0.002 mg / mL, about 0.003 mg / mL, about 0.004 mg / mL, about 0.005 mg / mL, about 0.006 mg / mL, about 0.007 mg / mL, about 0.008 mg / mL, about 0.009 mg / mL, about 0.01 mg / mL, about 0.02 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.06 mg / mL, about 0.07 mg / mL, about 0.08 mg / mL, about 0.09 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 125 mg / mL, about 150 mg / mL, about 175 mg / mL, about 200 mg / mL, about 250 mg / mL, about 300 mg / mL, about 350 mg / mL, about 400 mg / mL, about 450 mg / mL, about 500 mg / mL, about 550 mg / mL, about 600 mg / mL, about 650 mg / mL, about 700 mg / mL, about 750 mg / mL, about 800 mg / mL, about 850 mg / mL, about 900 mg / mL, about 950 mg / mL, about 1000 mg / mL, about 1050 mg / mL, about 1100 mg / mL, about 1150 mg / mL, about 1200 mg / mL, about 1250 mg / mL, about 1300 mg / mL, about 1350 mg / mL, about1400 mg / mL, about 1450 mg / mL, about 1500 mg / mL, about 1550 mg / mL, about 1600 mg / mL, about1650 mg / mL, about 1700 mg / mL, about 1750 mg / mL, about 1800 mg / mL, about 1850 mg / mL, about1900 mg / mL, about 1950 mg / mL, or about 2000 mg / mL.WSGR Docket No. 65156-703.601

[0270] A pharmaceutical composition provided herein can comprise an anti-aggregation agent. In some embodiments, the anti-aggregation agent is a polyol. In some embodiments, the anti -aggregation agent is a saccharide. In some embodiments, the anti -aggregation agent is a sugar. In some embodiments, the anti -aggregation agent is a sugar alcohol. In some embodiments, the anti -aggregation agent is maltitol, mannitol, isomalt, sorbitol, xylitol, or erythritol.

[0271] In some embodiments, the anti -aggregation agent is mannitol. In some embodiments, mannitol is present in the composition at a concentration from about 5 mM to about 200 mM. In some embodiments, mannitol is present in the composition at a concentration from about 50 mM to about 150 mM. In some embodiments, mannitol is present in the composition at a concentration from about 5 mM to about 30 mM. In some embodiments, mannitol is present in the composition at a concentration of 15 mM. In some embodiments, mannitol is present in the composition at a concentration of 100 mM.

[0272] In some embodiments, the anti-aggregation agent is a sugar. In some embodiments, the antiaggregation agent is a monosaccharide. In some embodiments, the anti -aggregation agent is dextrose. In some embodiments, dextrose is present in the composition at a concentration of about 50 mM to about 400 mM. In some embodiments, dextrose is present in the composition at a concentration of about 50 mM to about 300 mM. In some embodiments, dextrose is present in the composition at a concentration of about 200 mM to about 250 mM. In some embodiments, dextrose is present in the composition at a concentration of about 100 mM. In some embodiments, dextrose is present in the composition at a concentration of about 230 mM.

[0273] In some embodiments, a formulation provided herein comprises an amino acid, or a pharmaceutically acceptable salt or ionized form thereof. In some embodiments, the amino acid comprises a side chain that is positively charged at physiological pH. In some embodiments, the amino acid is histidine, lysine, ornithine, or arginine. In some embodiments, the amino acid is histidine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is ornithine. In some embodiments, the pharmaceutical composition further comprises a second amino acid or a pharmaceutically-acceptable salt or ionized form thereof. In some embodiments, the second amino acid comprises a side chain that is positively charged at physiological pH. In some embodiments, the second amino acid is arginine.

[0274] In some embodiments, the amino acid is a monomeric amino acid. In some embodiments, the amino acid is histidine, lysine, ornithine, or arginine. In some embodiments, the amino acid is histidine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is ornithine. In some embodiments, the pharmaceutical composition further comprises a second amino acid or a pharmaceutically-acceptable salt or ionized form thereof. In some embodiments, the second amino acid comprises a side chain that is positively charged at physiological pH. In some embodiments, the second amino acid is arginine.

[0275] In some embodiments, a formulation provided herein comprises a buffering agent. In some embodiments, the buffering agent is a dicarboxylic acid or a pharmaceutically acceptable salt or ionized form thereof. In some embodiments, the dicarboxylic acid is malonic acid, succinic acid, glutaric acid,WSGR Docket No. 65156-703.601 adipic acid, pimelic acid, or a pharmaceutically-acceptable salt thereof. In some embodiments, the buffering agent is succinic acid.

[0276] In some embodiments, the buffering agent is citric acid, acetic acid, boric acid, or phosphoric acid. In some embodiments, the buffering agent comprises a 1,2-aminoalcohol moiety. In some embodiments, the buffering agent is TAPS ([tris(hydroxymethyl)methylamino]propanesulfonic acid), Bicine (2-(bis(2-hydroxyethyl)amino)acetic acid), Tris (tris(hydroxymethyl)aminomethane), Tricine (N- [tris(hydroxymethyl)methyl]glycine), TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2- hydroxypropanesulfonic acid), HEPES (4-(2 -hydroxyethyl)- 1 -piperazineethanesulfonic acid), TES (2- [[l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid), or a pharmaceutically- acceptable salt thereof. In some embodiments, the buffering agent is an amino acid or a pharmaceutically acceptable salt thereof or ionized form thereof. In some embodiments, the amino acid maintains a pH of the composition of below about 7. In some embodiments, a composition of the present disclosure exhibits decreased aggregation in solutions with a pH of below about 7. In some embodiments, the amino acid is positively-charged at physiological pH. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is arginine. In some embodiments, a hydrophilic amino acid buffering agent is histidine. In some embodiments, the amino acid buffering agent is negatively-charged at physiological pH. In some embodiments, the negatively-charged amino acid buffer is an aspartic acid buffer. In some embodiments, the negatively-charged amino acid buffer is a glutamic acid buffer. In some embodiments, the amino acid buffer is a hydrophilic amino acid buffer. In some embodiments, the hydrophilic amino acid buffer is a serine buffer. In some embodiments, the hydrophilic amino acid buffer is a threonine buffer. In some embodiments, the hydrophilic amino acid buffer is a tyrosine buffer. In some embodiments, the hydrophilic amino acid buffer is an asparagine amino acid buffer. In some embodiments, the hydrophilic amino acid buffer is a glutamine buffer.

[0277] In some embodiments, the amino acid is a hydrophobic amino acid. In some embodiments, the hydrophobic amino acid is valine. In some embodiments, the hydrophobic amino acid buffer is a leucine buffer. In some embodiments, the hydrophobic amino acid buffer is an isoleucine buffer. In some embodiments, the hydrophobic amino acid buffer is a methionine buffer. In some embodiments, the hydrophobic amino acid buffer is a phenylalanine buffer. In some embodiments, the hydrophobic amino acid buffer is a glycine buffer. In some embodiments, the hydrophobic amino acid buffer is an alanine buffer. In some embodiments, the hydrophobic amino acid buffer is a cysteine buffer. In some embodiments, the hydrophobic amino acid buffer is a proline buffer. In some embodiments, the hydrophobic amino acid buffer is a tryptophan buffer.

[0278] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of at least about 0.001 mg / mL, at least about 0.002 mg / mL, at least about 0.003 mg / mL, at least about 0.004 mg / mL, at least about 0.005 mg / mL, at least about 0.006 mg / mL, at least about 0.007 mg / mL, at least about 0.008 mg / mL, at least about 0.009 mg / mL, at least about 0.01 mg / mL, at least about 0.02 mg / mL, at least about 0.03 mg / mL, at least about 0.04 mg / mL, at least about 0.05 mg / mL, at least about 0.06 mg / mL, at least about 0.07 mg / mL, at least about 0.08 mg / mL, at least about 0.09WSGR Docket No. 65156-703.601 mg / mL, at least about 0.1 mg / mL, at least about 0.2 mg / mL, at least about 0.3 mg / mL, at least about 0.4 mg / mL, at least about 0.5 mg / mL, at least about 0.6 mg / mL, at least about 0.7 mg / mL, at least about 0.8 mg / mL, at least about 0.9 mg / mL, at least about 1 mg / mL, at least about 2 mg / mL, at least about 3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 10 mg / mL, at least about 15 mg / mL, at least about 20 mg / mL, at least about 25 mg / mL, at least about 30 mg / mL, at least about 35 mg / mL, at least about 40 mg / mL, at least about 45 mg / mL, at least about 50 mg / mL, at least about 55 mg / mL, at least about 60 mg / mL, at least about 65 mg / mL, at least about 70 mg / mL, at least about 75 mg / mL, at least about 80 mg / mL, at least about 85 mg / mL, at least about 90 mg / mL, at least about 95 mg / mL, at least about 100 mg / mL, at least about 125 mg / mL, at least about 150 mg / mL, at least about 175 mg / mL, at least about 200 mg / mL, at least about 250 mg / mL, at least about 300 mg / mL, at least about 350 mg / mL, at least about 400 mg / mL, at least about 450 mg / mL, at least about 500 mg / mL, at least about 550 mg / mL, at least about 600 mg / mL, at least about 650 mg / mL, at least about 700 mg / mL, at least about 750 mg / mL, at least about 800 mg / mL, at least about 850 mg / mL, at least about 900 mg / mL, at least about 950 mg / mL, at least about 1000 mg / mL, at least about 1050 mg / mL, at least about 1100 mg / mL, at least about 1150 mg / mL, at least about 1200 mg / mL, at least about 1250 mg / mL, at least about 1300 mg / mL, at least about 1350 mg / mL, at least about 1400 mg / mL, at least about 1450 mg / mL, at least about 1500 mg / mL, at least about 1550 mg / mL, at least about 1600 mg / mL, at least about 1650 mg / mL, at least about 1700 mg / mL, at least about 1750 mg / mL, at least about 1800 mg / mL, at least about 1850 mg / mL, at least about 1900 mg / mL, at least about 1950 mg / mL, or at least about 2000 mg / mL.

[0279] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of at most about 0.002 mg / mL, at most about 0.003 mg / mL, at most about 0.004 mg / mL, at most about 0.005 mg / mL, at most about 0.006 mg / mL, at most about 0.007 mg / mL, at most about 0.008 mg / mL, at most about 0.009 mg / mL, at most about 0.01 mg / mL, at most about 0.02 mg / mL, at most about 0.03 mg / mL, at most about 0.04 mg / mL, at most about 0.05 mg / mL, at most about 0.06 mg / mL, at most about 0.07 mg / mL, at most about 0.08 mg / mL, at most about 0.09 mg / mL, at most about 0.1 mg / mL, at most about 0.2 mg / mL, at most about 0.3 mg / mL, at most about 0.4 mg / mL, at most about 0.5 mg / mL, at most about 0.6 mg / mL, at most about 0.7 mg / mL, at most about 0.8 mg / mL, at most about 0.9 mg / mL, at most about 1 mg / mL, at most about 2 mg / mL, at most about 3 mg / mL, at most about 4 mg / mL, at most about 5 mg / mL, at most about 10 mg / mL, at most about 15 mg / mL, at most about 20 mg / mL, at most about 25 mg / mL, at most about 30 mg / mL, at most about 35 mg / mL, at most about 40 mg / mL, at most about 45 mg / mL, at most about 50 mg / mL, at most about 55 mg / mL, at most about 60 mg / mL, at most about 65 mg / mL, at most about 70 mg / mL, at most about 75 mg / mL, at most about 80 mg / mL, at most about 85 mg / mL, at most about 90 mg / mL, at most about 95 mg / mL, at most about 100 mg / mL, at most about 125 mg / mL, at most about 150 mg / mL, at most about 175 mg / mL, at most about 200 mg / mL, at most about 250 mg / mL, at most about 300 mg / mL, at most about 350 mg / mL, at most about 400 mg / mL, at most about 450 mg / mL, at most about 500 mg / mL, at most about 550 mg / mL, at most about 600 mg / mL, at most about 650 mg / mL, at most about 700 mg / mL, at most about 750 mg / mL,WSGR Docket No. 65156-703.601 at most about 800 mg / mL, at most about 850 mg / mL, at most about 900 mg / mL, at most about 950 mg / mL, at most about 1000 mg / mL, at most about 1050 mg / mL, at most about 1100 mg / mL, at most about 1150 mg / mL, at most about 1200 mg / mL, at most about 1250 mg / mL, at most about 1300 mg / mL, at most about 1350 mg / mL, at most about 1400 mg / mL, at most about 1450 mg / mL, at most about 1500 mg / mL, at most about 1550 mg / mL, at most about 1600 mg / mL, at most about 1650 mg / mL, at most about 1700 mg / mL, at most about 1750 mg / mL, at most about 1800 mg / mL, at most about 1850 mg / mL, at most about 1900 mg / mL, at most about 1950 mg / mL, or at most about 2000 mg / mL.

[0280] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of about 1 mg / mL to about 2000 mg / mL; from about 5 mg / mL to about 1000 mg / mL, from about 10 mg / mL to about 25 mg / mL, from about 50 mg / mL to about 250 mg / mL, from about 100 mg / mL to about 200 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 50 mg / mL to about 100 mg / mL, from about 100 mg / mL to about 150 mg / mL, from about 150 mg / mL to about 200 mg / mL, from about 200 mg / mL to about 250 mg / mL, from about 250 mg / mL to about 300 mg / mL, from about 300 mg / mL to about 350 mg / mL, from about 350 mg / mL to about 400 mg / mL, from about 400 mg / mL to about 450 mg / mL, from about 450 mg / mL to about 500 mg / mL, from about 500 mg / mL to about 550 mg / mL, from about 550 mg / mL to about 600 mg / mL, from about 600 mg / mL to about 650 mg / mL, from about 650 mg / mL to about 700 mg / mL, from about 700 mg / mL to about 750 mg / mL, from about 750 mg / mL to about 800 mg / mL, from about 800 mg / mL to about 850 mg / mL, from about 850 mg / mL to about 900 mg / mL, from about 900 mg / mL to about 950 mg / mL, from about 950 mg / mL to about 1000 mg / mL, about 1 pg / mL to about 2000 pg / mL; from about 5 pg / mL to about 1000 pg / mL, from about 10 pg / mL to about 25 pg / mL, from about 50 pg / mL to about 250 pg / mL, from about 100 pg / mL to about 200 pg / mL, from about 1 pg / mL to about 50 pg / mL, from about 50 pg / mL to about 100 pg / mL, from about 100 pg / mL to about 150 pg / mL, from about 150 pg / mL to about 200 pg / mL, from about 200 pg / mL to about 250 pg / mL, from about 250 pg / mL to about 300 pg / mL, from about 300 pg / mL to about 350 pg / mL, from about 350 pg / mL to about 400 pg / mL, from about 400 pg / mL to about 450 pg / mL, from about 450 pg / mL to about 500 pg / mL, from about 500 pg / mL to about 550 pg / mL, from about 550 pg / mL to about 600 pg / mL, from about 600 pg / mL to about 650 pg / mL, from about 650 pg / mL to about 700 pg / mL, from about 700 pg / mL to about 750 pg / mL, from about 750 pg / mL to about 800 pg / mL, from about 800 pg / mL to about 850 pg / mL, from about 850 pg / mL to about 900 pg / mL, from about 900 pg / mL to about 950 pg / mL, or from about 950 pg / mL to about 1000 pg / mL.

[0281] A compound as described herein can be present in a composition with a defined pH range. The pH of the pharmaceutical compositions can be adjusted to a value near physiological pH. In some embodiments, the physiological pH is about 7 to about 7.8. In some embodiments, the pH range of the pharmaceutical composition is from about 1 to about 9, from about 1 to about 2, from about 2 to about 8, from about 2 to about 3, from about 3 to about 8, from about 3 to about 4, from about 4 to about 8, from about 4 to about 5, from about 5 to about 7.5, from about 5 to about 8, from about 5 to about 5.5, from about 5.5 to about 8, from about 5.5 to about 7.5, from about 5.5 to about 6, from about 6 to about 8, from about 6 to about 7.5, from about 6 to about 7, from about 7 to about 8, from about 7 to 7.5, or fromWSGR Docket No. 65156-703.601 about 7 to about 7.8. In some embodiments, the pH range of the pharmaceutical composition is from about 5 to about 7.5. In some embodiments, the pH of the pharmaceutical composition is at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 3.5, at least about 4, at least about 4.5, at least about 5, at least about 5.5, at least about 6, at least about 6.5, at least about 7, at least about 7.5, at least about 7.8, or at least about 8, or more. In some embodiments, the pH of the pharmaceutical composition is a pH of at most about 8, at most about 7.8, at most about 7.5, at most about 7, at most about 6.5, at most about 6, at most about 5.5, at most about 5, at most about 4.5, at most about 4, at most about 3.5, at most about 3, at most about 2.5, at most about 2, at most about 1.5, at most about 1, or less. In some embodiments, the pH of the pharmaceutical composition is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 7.8, or about 8. In some embodiments, the pH of the pharmaceutical composition is about 5. In some embodiments, the pH of the pharmaceutical composition is about 5.5. In some embodiments, the pH of the pharmaceutical composition is about 6. In some embodiments, the pH of the pharmaceutical composition is about 6.5. In some embodiments, the pH of the pharmaceutical composition is about 7. In some embodiments, the pH of the pharmaceutical composition is about 7.5. In some embodiments, the pH of the pharmaceutical composition is about 7.8.

[0282] In some embodiments, the pH of the pharmaceutical composition is measured by a commercially available pH meter.Methods of treatment.

[0283] The present disclosure describes the use of a compound and methods to treat conditions or genetic disease, including repeat expansion diseases. The method can comprise administering to the subject a therapeutically-effective amount of a compound of the disclosure. In some embodiments, the repeat expansion disease is a polyglutamine disease, Fragile X-associated ataxia syndrome, fragile X syndrome, myotonic dystrophy type 1 (DM1), Huntington disease-like 2, spinocerebellar ataxia type 8, Fuchs corneal dystrophy, Friedreich ataxia, Fragile XE syndrome, FRA16A (CGG)n repeat expansion, oculopharyngeal muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, spinocerebellar ataxia type 10, spinocerebellar ataxia type 31, spinocerebellar ataxia type 36, C9ORF72 frontotemporal dementia, or progressive myoclonic epilepsy type 1. In some embodiments, the repeat expansion disease is myotonic dystrophy type 1.

[0284] In some embodiments, the repeat expansion disease is a polyglutamine disease. In some embodiments, the polyglutamine disease is Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, or spinocerebellar ataxia type 17.

[0285] In some embodiments, the polyglutamine disease is Huntington’s disease. Huntington’s disease is an inherited gain-of-function disease associated by expansion of a translated CAG repeat in the huntingtin gene (HTT). The number of CAG repeats in a gene can be variable in the general population,WSGR Docket No. 65156-703.601 for example, the number of CAG repeats in HD can be in a range of about 6 to about 35 repeats in subjects that do not have HD. The number of CAG repeats in subjects with HD can be at least 36 and in some cases upwards of 100. In some embodiments, the efficacy of a compound, composition, or method of the disclosure can vary based on the number of repeats in the gene or locus.

[0286] In some embodiments, the present disclosure provides a method of treating a subject suffering from a polyglutamine disease, comprising administering to the subject a compound herein. In some embodiments, the polyglutamine disease is Huntington’s disease. In some embodiments, the subject has a HTT gene with an expanded repeat region. In some embodiments, the expanded repeat region is from about 35 to about 1000 CAG repeats in size. In some embodiments, the expanded repeat region is from about 35 to about 2000 CAG repeats in size. In some embodiments, the expanded repeat region is from 27 to 36, from 27 to 36, from 27 to 40, from 27 to 60, from 27 to 80, from 27 to 90, from 36 to 40, from 36 to 60, from 36 to 80, from 36 to 90, from 40 to 60, from 40 to 80, from 40 to 90, or from 60 to 90 CAG repeats in size.

[0287] In some embodiments, the polyglutamine disease is Huntington’s disease, and the subject has a HTT gene with an expanded repeat region that is at least 36, at least 37, at least 38, at least 40, at least 41, at least 44, at least 50, at least 53, at least 60, at least 70, at least 76, at least 80, at least 90, at least 100, at least 150, or at least 200 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 36 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 37 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 38 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 40 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 41 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 44 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 50 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 53 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 60 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 70 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 76 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 80 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 90 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 100 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 150 CAG repeats in size. In some embodiments, the expanded repeat region is at least about 200 CAG repeats in size.

[0288] In some embodiments, the polyglutamine disease is Huntington’s disease, and the subject has a HTT gene with an expanded repeat region that is no more than about 200 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 151 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 150 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 125 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 100 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 90 CAG repeats in size. In someWSGR Docket No. 65156-703.601 embodiments, the expanded repeat region is no more than about 80 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 76 CAG repeats in size. In some embodiments, the expanded repeat region is no more than about 70 CAG repeats in size.

[0289] In some embodiments, the polyglutamine disease is Huntington’s disease, and the subject has a HTT gene with an expanded repeat region that is from about 36 to about 100 CAG repeats in size. In some embodiments, the expanded repeat region is from about 36 to about 125 CAG repeats in size. In some embodiments, the expanded repeat region is from about 36 to about 150 CAG repeats in size. In some embodiments, the expanded repeat region is from about 36 to about 200 CAG repeats in size. In some embodiments, the expanded repeat region is from about 36 to about 500 CAG repeats in size. In some embodiments, the expanded repeat region is from about 36 to about 1000 CAG repeats in size. In some embodiments, the expanded repeat region is from about 36 to about 2000 CAG repeats in size.

[0290] In some embodiments, the repeat expansion disease is myotonic dystrophy type 1 (DM1), which is associated with an expanded number of CTG repeats in the DMPK gene on chromosome 19 q 13.3. Subjects with a DMPK gene with a repeat size between 38 and 49 are generally asymptomatic, while repeats sizes of 50 to 150 are associated with mild DM1. Repeats in the range of 50 to 1,000 are seen in individuals with classic DM1. CTG repeat lengths greater than 800 may manifest as childhood DM1. With CTG repeat lengths greater than 1,000, DM1 may manifest as congenital MD.

[0291] In some embodiments, the present disclosure provides a method of treating a subject suffering from myotonic dystrophy type 1 (DM1), comprising administering to the subject a compound herein. In some embodiments, the subject has a DMPK gene with an expanded repeat region. In some embodiments, the expanded repeat region is at least 50, at least 100, at least 200, at least 500, at least 800, or at least 1000 CTG repeats in size. In some embodiments, the expanded repeat region is at least about 50 CTG repeats in size. In some embodiments, the expanded repeat region is at least about 800 CTG repeats in size. In some embodiments, the expanded repeat region is at least about 1000 CTG repeats in size. In some embodiments, the expanded repeat region is at least about 50 CTG repeats in size. In some embodiments, the expanded repeat region is from 50 to 2000 CTG repeats in size. In some embodiments, the expanded repeat region is from 1000 to 2000 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 2000 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 1000 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 800 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 500 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 250 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 150 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 100 CTG repeats in size. In some embodiments, the expanded repeat region is no more than about 50 CTG repeats in size.

[0292] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered to a subject in various forms and by various suitable routes of administration.WSGR Docket No. 65156-703.601

[0293] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in a systemic manner.

[0294] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered parenterally. Parenteral administration can be, for example, by bolus injection or by gradual infusion or perfusion over time. Administration can also be by surgical deposition of a bolus or positioning of a medical device.

[0295] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered orally. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by an intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intracerebroventricular, intra-articular, intraperitoneal, intracranial, intrathecal, intranasal, buccal, sublingual, oral, or rectal administration route. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intravenous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by subcutaneous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intracerebroventricular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by oral administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intrathecal administration.

[0296] Any aforementioned route of administration can be combined with another route of administration. For example, a compound provided herein can be delivered by a first route of administration, and one or more subsequent maintenance doses of the compound can be delivered by the same or a different route of administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration, and one or more subsequent maintenance doses of the compound or the composition comprising the compound are delivered by subcutaneous administration or intravenous administration.

[0297] Non-limiting examples of suitable modes and routes of administration include oral, topical, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion,WSGR Docket No. 65156-703.601 intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid infusion, intraocular injection, intraspinal injection, intrastemal injection, ophthalmic administration, endothelial administration, local administration, intranasal administration, intrapulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, transdermal administration (e.g., via emulsion / liposome-mediated methods of delivery with the compound optionally packaged into liposomes), epidural administration, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa), intracapsular administration, subcapsular administration, intracardiac administration, transtracheal administration, subcuticular administration, subarachnoid administration, subcapsular administration, intraspinal administration, and intrastemal administration.

[0298] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered via a non-invasive method. Examples of non-invasive modes of administering can include using a needleless injection device, and topical administration, e.g., eye drops. Multiple administration routes can be employed for efficient delivery.

[0299] Depending on the intended mode of administration, the compositions can be in the form of solid, semi solid or liquid dosage forms, such as, e.g., tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, e.g., in unit dosage form suitable for single administration of a precise dosage. The composition can be formulated into any suitable dosage form for administration, e.g., aqueous dispersions, liquids, gels, syrups, elixirs, slurries, and suspensions, for administration to a subject or a patient.

[0300] Solid compositions include, e.g., powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, e.g., solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, e.g., gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically- acceptable additives.

[0301] In some embodiments, the composition is formulated into solutions (e.g., for IV administration). In some cases, the pharmaceutical composition is formulated as an infusion. In some cases, the pharmaceutical composition is formulated as an injection.

[0302] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release.WSGR Docket No. 65156-703.601

[0303] A composition comprising a compound provided herein can be, e.g., an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profdes of the active agent can be matched to physiological and chronotherapeutic requirements, or has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gelforming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0304] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, e.g., for about 4, about 8, about 12, about 16, or about 24 hours. A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, e.g., the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profde) over about 4, about 8, about 12, about 16, or about 24 hours.

[0305] A pharmaceutical composition disclosed herein can be targeted to any suitable tissue or cell type. Modes, routes, and compositions provided herein can be suitable to target a compound provided herein to a particular tissue, or a subset of tissues. Non-limiting examples of tissues that can be targeted include kidney (e.g., kidney cortex), joints, cartilage, liver, salivary glands, bone (e.g., bone surface), skin, lung, muscle, pancreas, hair follicles, large intestine mucosa, aortic wall, small intestine mucosa, adrenal gland, stomach mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate putamen, cerebral cortex, substantia nigra, lateral ventricle, choroid plexus, and combinations thereof.

[0306] Compounds can be introduced into cells by, e.g., transfection, electroporation, fusion, liposomes, colloidal polymeric particles, and viral and non-viral vectors. Compounds provided herein can also be delivered using, e.g., methods involving liposome-mediated uptake, lipid conjugates, polylysine- mediated uptake, nanoparticle-mediated uptake, and receptor-mediated endocytosis, as well as additional non-endocytic modes of delivery, such as microinjection, permeabilization (e.g., streptolysin-0 permeabilization, anionic peptide permeabilization), electroporation, and various non-invasive non- endocytic methods of delivery.

[0307] The method of delivery can depend at least on the cells to be treated and the location of the cells. For instance, localization can be achieved by liposomes with specific markers on the surface to direct the liposome, direct injection into tissue containing target cells, specific receptor mediated uptake, or viral vectors.WSGR Docket No. 65156-703.601

[0308] In some embodiments, a compound disclosed herein is delivered via an implantable device, e.g., synthetic implant design.

[0309] Compounds provided herein can be administered in any physiologically and / or pharmaceutically acceptable vehicle or carrier. Non-limiting examples of pharmaceutically acceptable carriers include saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions, such as oil / water emulsions or triglyceride emulsions, tablets, and capsules. The choice of suitable physiologically acceptable carrier can vary depending upon the chosen mode of administration. A pharmaceutically acceptable carrier can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0310] Further provided are prodrugs of a compound provided herein. Prodrugs can be covalently bonded carriers that release a compound in vivo when administered to a subject. Prodrugs can be prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, to yield the biologically active compound. Non-limiting examples of prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups of compounds provided herein. Further, in the case of a carboxylic acid functional group ( — COOH), esters can be used, such as methyl esters and ethyl esters.

[0311] In some embodiments, liposomes can be used to facilitate uptake of a compound provided herein into cells. Hydrogels can also be used as vehicles for compound administration. Alternatively, a compound provided herein can be administered in microspheres or microparticles. Alternatively, the use of gas-fdled microbubbles complexed with a compound provided herein can enhance delivery to target tissues. Sustained release compositions can also be used, including, e.g., semipermeable polymeric matrices in the form of shaped articles such as fdms or microcapsules.

[0312] In some embodiments, a compound provided herein is administered to a mammalian subject, e.g., human or domestic animal that is exhibiting the symptoms of a polynucleotide repeat expansion disorder. Compounds provided herein can selectively reduce expression of a mutant protein in the subject. In some embodiments, the subject is a human subject, e.g., a patient diagnosed as having a polynucleotide repeat disease. In some embodiments, a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered orally. In some embodiments, a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered intravenously.

[0313] In some embodiments, the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.

[0314] In some embodiments, the patient is a vertebrate. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat,WSGR Docket No. 65156-703.601 hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a patient is a non-human patient. In some embodiments, a patient is a veterinary patient.

[0315] In some embodiments, a patient and a subject are the same species. In some embodiments, a subject and a patient are human.

[0316] In some embodiments, a patient and a subject are different species. In some embodiments, a subject is human and a patient is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig. In some embodiments, a patient is human and a subject is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea Pig-

[0317] An effective in vivo treatment regimen using the compounds provided herein can vary according to the duration, dose, frequency, and route of administration, as well as the condition of the subject under treatment (i.e., prophylactic administration versus administration in response to localized or systemic infection). Accordingly, such in vivo therapy can require monitoring by tests appropriate to the particular type of disorder under treatment, and corresponding adjustments in the dose or treatment regimen, in order to achieve an optimal therapeutic outcome.

[0318] The efficacy of an in vivo administered compound provided herein can be determined from biological samples (e.g., tissue, blood, urine) taken from a subject prior to, during, and subsequent to administration of the compound. Assays of such samples can include (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences, e.g., by an electrophoretic gel mobility assay; and (2) monitoring the amount of a mutant mRNA or protein in relation to a reference wild-type mRNA or protein as determined by standard techniques such as RT-PCR, Northern blotting, ELISA, or Western blotting.

[0319] In some embodiments, the compound provided herein is actively taken up by mammalian cells. In further embodiments, the compound provided herein can be conjugated to a transport moiety (e.g., transport peptide) as described herein to facilitate such uptake.

[0320] Compounds provided herein can be administered to subjects to treat (prophylactically or therapeutically) disorders associated with aberrant expression of a mRNA or protein produced from a mutant polynucleotide repeat containing allele. In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual’s genotype and the individual’s response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a therapeutic agent as well as tailoring the dosage and / or therapeutic regimen of treatment with the therapeutic agent.WSGR Docket No. 65156-703.601Dosing.

[0321] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The dosage (e.g., therapeutically-effective amount) for a compound described herein can be in any amount necessary.

[0322] A compound described herein can be present in a composition or a unit dose in a range of from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 25 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.

[0323] A compound described herein can be present in a composition or a unit dose in a range of from about 1 pg to about 2000 pg; from about 5 pg to about 1000 pg, from about 10 pg to about 25 pg, from about 50 pg to about 250 pg, from about 100 pg to about 200 pg, from about 1 pg to about 50 pg, from about 50 pg to about 100 pg, from about 100 pg to about 150 pg, from about 150 pg to about 200 pg, from about 200 pg to about 250 pg, from about 250 pg to about 300 pg, from about 300 pg to about 350 pg, from about 350 pg to about 400 pg, from about 400 pg to about 450 pg, from about 450 pg to about 500 pg, from about 500 pg to about 550 pg, from about 550 pg to about 600 pg, from about 600 pg to about 650 pg, from about 650 pg to about 700 pg, from about 700 pg to about 750 pg, from about 750 pg to about 800 pg, from about 800 pg to about 850 pg, from about 850 pg to about 900 pg, from about 900 pg to about 950 pg, or from about 950 pg to about 1000 pg.

[0324] A compound described herein can be present in a composition or a unit dose in an amount of about 0.001 mg, about 0.002 mg, about 0.003 mg, about 0.004 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, aboutWSGR Docket No. 65156-703.6011300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0325] In some embodiments, a composition is present in a composition or a unit dose in an amount that is at least about 0.001 mg, at least about 0.002 mg, at least about 0.003 mg, at least about 0.004 mg, at least about 0.005 mg, at least about 0.006 mg, at least about 0.007 mg, at least about 0.008 mg, at least about 0.009 mg, at least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, or at least about 2000 mg.

[0326] In some embodiments, a composition is present in a composition or a unit dose in an amount that is at most about 0.001 mg, at most about 0.002 mg, at most about 0.003 mg, at most about 0.004 mg, at most about 0.005 mg, at most about 0.006 mg, at most about 0.007 mg, at most about 0.008 mg, at most about 0.009 mg, at most about 0.01 mg, at most about 0.02 mg, at most about 0.03 mg, at most about 0.04 mg, at most about 0.05 mg, at most about 0.06 mg, at most about 0.07 mg, at most about 0.08 mg, at most about 0.09 mg, at most about 0.1 mg, at most about 0.2 mg, at most about 0.3 mg, at most about 0.4 mg, at most about 0.5 mg, at most about 0.6 mg, at most about 0.7 mg, at most about 0.8 mg, at most about 0.9 mg, at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 125 mg, at most about 150 mg, at most about 175 mg, at most about 200 mg, at most about 250 mg, at most about 300 mg, at most about 350 mg, at most about 400 mg, at most aboutWSGR Docket No. 65156-703.601450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, at most about 1000 mg, at most about 1050 mg, at most about 1100 mg, at most about 1150 mg, at most about 1200 mg, at most about 1250 mg, at most about 1300 mg, at most about 1350 mg, at most about 1400 mg, at most about 1450 mg, at most about 1500 mg, at most about 1550 mg, at most about 1600 mg, at most about 1650 mg, at most about 1700 mg, at most about 1750 mg, at most about 1800 mg, at most about 1850 mg, at most about 1900 mg, at most about 1950 mg, or at most about 2000 mg.

[0327] In some embodiments, a dose (e.g., a unit dose) is about 0.001 mg / kg, about 0.002 mg / kg, about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0. 1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, about 1000 mg / kg, about 1050 mg / kg, about 1100 mg / kg, about 1150 mg / kg, about 1200 mg / kg, about 1250 mg / kg, about 1300 mg / kg, about 1350 mg / kg, about 1400 mg / kg, about 1450 mg / kg, about 1500 mg / kg, about 1550 mg / kg, about 1600 mg / kg, about 1650 mg / kg, about 1700 mg / kg, about 1750 mg / kg, about 1800 mg / kg, about 1850 mg / kg, about 1900 mg / kg, about 1950 mg / kg, or about 2000 mg / kg based on body mass of a subject or a patient.

[0328] In some embodiments, a dose (e.g., a unit dose) is at least about 0.001 mg / kg, at least about 0.002 mg / kg, at least about 0.003 mg / kg, at least about 0.004 mg / kg, at least about 0.005 mg / kg, at least about 0.006 mg / kg, at least about 0.007 mg / kg, at least about 0.008 mg / kg, at least about 0.009 mg / kg, at least about 0.01 mg / kg, at least about 0.02 mg / kg, at least about 0.03 mg / kg, at least about 0.04 mg / kg, at least about 0.05 mg / kg, at least about 0.06 mg / kg, at least about 0.07 mg / kg, at least about 0.08 mg / kg, at least about 0.09 mg / kg, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1 mg / kg, at least about 2 mg / kg, at least about 3 mg / kg, at least about 4 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80WSGR Docket No. 65156-703.601 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, at least about 100 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 175 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 400 mg / kg, at least about 450 mg / kg, at least about 500 mg / kg, at least about 550 mg / kg, at least about 600 mg / kg, at least about 650 mg / kg, at least about 700 mg / kg, at least about 750 mg / kg, at least about 800 mg / kg, at least about 850 mg / kg, at least about 900 mg / kg, at least about 950 mg / kg, at least about 1000 mg / kg, at least about 1050 mg / kg, at least about 1100 mg / kg, at least about 1150 mg / kg, at least about 1200 mg / kg, at least about 1250 mg / kg, at least about 1300 mg / kg, at least about 1350 mg / kg, at least about 1400 mg / kg, at least about 1450 mg / kg, at least about 1500 mg / kg, at least about 1550 mg / kg, at least about 1600 mg / kg, at least about 1650 mg / kg, at least about 1700 mg / kg, at least about 1750 mg / kg, at least about 1800 mg / kg, at least about 1850 mg / kg, at least about 1900 mg / kg, at least about 1950 mg / kg, or at least about 2000 mg / kg based on body mass of a subject or a patient.

[0329] In some embodiments, a dose (e.g., a unit dose) is at most about 0.001 mg / kg, at most about 0.002 mg / kg, at most about 0.003 mg / kg, at most about 0.004 mg / kg, at most about 0.005 mg / kg, at most about 0.006 mg / kg, at most about 0.007 mg / kg, at most about 0.008 mg / kg, at most about 0.009 mg / kg, at most about 0.01 mg / kg, at most about 0.02 mg / kg, at most about 0.03 mg / kg, at most about 0.04 mg / kg, at most about 0.05 mg / kg, at most about 0.06 mg / kg, at most about 0.07 mg / kg, at most about 0.08 mg / kg, at most about 0.09 mg / kg, at most about 0. 1 mg / kg, at most about 0.2 mg / kg, at most about 0.3 mg / kg, at most about 0.4 mg / kg, at most about 0.5 mg / kg, at most about 0.6 mg / kg, at most about 0.7 mg / kg, at most about 0.8 mg / kg, at most about 0.9 mg / kg, at most about 1 mg / kg, at most about 2 mg / kg, at most about 3 mg / kg, at most about 4 mg / kg, at most about 5 mg / kg, at most about 10 mg / kg, at most about 15 mg / kg, at most about 20 mg / kg, at most about 25 mg / kg, at most about 30 mg / kg, at most about 35 mg / kg, at most about 40 mg / kg, at most about 45 mg / kg, at most about 50 mg / kg, at most about 55 mg / kg, at most about 60 mg / kg, at most about 65 mg / kg, at most about 70 mg / kg, at most about 75 mg / kg, at most about 80 mg / kg, at most about 85 mg / kg, at most about 90 mg / kg, at most about 95 mg / kg, at most about 100 mg / kg, at most about 125 mg / kg, at most about 150 mg / kg, at most about 175 mg / kg, at most about 200 mg / kg, at most about 250 mg / kg, at most about 300 mg / kg, at most about 350 mg / kg, at most about 400 mg / kg, at most about 450 mg / kg, at most about 500 mg / kg, at most about 550 mg / kg, at most about 600 mg / kg, at most about 650 mg / kg, at most about 700 mg / kg, at most about 750 mg / kg, at most about 800 mg / kg, at most about 850 mg / kg, at most about 900 mg / kg, at most about 950 mg / kg, at most about 1000 mg / kg, at most about 1050 mg / kg, at most about 1100 mg / kg, at most about 1150 mg / kg, at most about 1200 mg / kg, at most about 1250 mg / kg, at most about 1300 mg / kg, at most about 1350 mg / kg, at most about 1400 mg / kg, at most about 1450 mg / kg, at most about 1500 mg / kg, at most about 1550 mg / kg, at most about 1600 mg / kg, at most about 1650 mg / kg, at most about 1700 mg / kg, at most about 1750 mg / kg, at most about 1800 mg / kg, at most about 1850 mg / kg, at most about 1900 mg / kg, at most about 1950 mg / kg, or at most about 2000 mg / kg based on body mass of a subject or a patient.WSGR Docket No. 65156-703.601

[0330] In some embodiments, a dose (e.g., a unit dose) is from about 0.1 mg / kg to about 2000 mg / kg, from about 1 mg / kg to about 2000 mg / kg, from about 5 mg / kg to about 1000 mg / kg, from about 10 mg / kg to about 25 mg / kg, from about 50 mg / kg to about 250 mg / kg, from about 100 mg / kg to about 200 mg / kg, from about 1 mg / kg to about 50 mg / kg, from about 50 mg / kg to about 100 mg / kg, from about 100 mg / kg to about 150 mg / kg, from about 150 mg / kg to about 200 mg / kg, from about 200 mg / kg to about 250 mg / kg, from about 250 mg / kg to about 300 mg / kg, from about 300 mg / kg to about 350 mg / kg, from about 350 mg / kg to about 400 mg / kg, from about 400 mg / kg to about 450 mg / kg, from about 450 mg / kg to about 500 mg / kg, from about 500 mg / kg to about 550 mg / kg, from about 550 mg / kg to about 600 mg / kg, from about 600 mg / kg to about 650 mg / kg, from about 650 mg / kg to about 700 mg / kg, from about 700 mg / kg to about 750 mg / kg, from about 750 mg / kg to about 800 mg / kg, from about 800 mg / kg to about 850 mg / kg, from about 850 mg / kg to about 900 mg / kg, from about 900 mg / kg to about 950 mg / kg, from about 950 mg / kg to about 1000 mg / kg, about 1 gg / kg to about 2000 gg / kg; from about 5 gg / kg to about 1000 gg / kg, from about 10 gg / kg to about 25 gg / kg, from about 50 gg / kg to about 250 gg / kg, from about 100 gg / kg to about 200 gg / kg, from about 1 gg / kg to about 50 gg / kg, from about 50 gg / kg to about 100 gg / kg, from about 100 gg / kg to about 150 gg / kg, from about 150 gg / kg to about 200 gg / kg, from about 200 gg / kg to about 250 gg / kg, from about 250 gg / kg to about 300 gg / kg, from about 300 gg / kg to about 350 gg / kg, from about 350 gg / kg to about 400 gg / kg, from about 400 gg / kg to about 450 gg / kg, from about 450 gg / kg to about 500 gg / kg, from about 500 gg / kg to about 550 gg / kg, from about 550 gg / kg to about 600 gg / kg, from about 600 gg / kg to about 650 gg / kg, from about 650 gg / kg to about 700 gg / kg, from about 700 gg / kg to about 750 gg / kg, from about 750 gg / kg to about 800 gg / kg, from about 800 gg / kg to about 850 gg / kg, from about 850 gg / kg to about 900 gg / kg, from about 900 gg / kg to about 950 gg / kg, or from about 950 gg / kg to about 1000 gg / kg based on body mass of a subject or a patient.NUMBERED EMBODIMENTS

[0331] The following numbered embodiments are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0332] 1. A compound of formula (VI), or a pharmaceutically-acceptable salt or ionized form thereof:usfvnwherein:A-Terminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence; C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, orNH2; each of PEP1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent;WSGR Docket No. 65156-703.601- Z is -(Ul)(X5)-xY-(X8)(X9)-YYx-(X13)(X14)(X15)(X16)-Y-(U2)-;- U1 is -Yx-(X3)(X4)-, -x-(X3)(X4)-, -(X3)(X4)-, -(X4)-, or absent;U2 is -x-(X19)-, -x-, or absent;- each of X3, X4, X5, X8, X9, X12, X13, X14, X15, X16, and X19 is independently Y or x;each R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH.

[0333] 2. The compound of embodiment 1, wherein X3 is x.

[0334] 3. The compound of embodiment 1, wherein X3 is Y.

[0335] 4. The compound of embodiment 1 or 2, wherein X4 is x.

[0336] 5. The compound of embodiment 1 or 2, wherein X4 is Y.

[0337] 6. The compound of any one of embodiments 1-5, wherein X5 is x.

[0338] 7. The compound of any one of embodiments 1-5, wherein X5 is Y.

[0339] 8. The compound of any one of embodiments 1-7, wherein X8 is x.

[0340] 9. The compound of any one of embodiments 1-7, wherein X8 is Y.

[0341] 10. The compound of any one of embodiments 1-9, wherein X9 is x.

[0342] 11. The compound of any one of embodiments 1-9, wherein X9 is Y.

[0343] 12. The compound of any one of embodiments 1-11, wherein X12 is x.

[0344] 13. The compound of any one of embodiments 1-11, wherein X12 is Y.

[0345] 14. The compound of any one of embodiments 1-13, wherein X13 is x.

[0346] 15. The compound of any one of embodiments 1-13, wherein X13 is Y.

[0347] 16. The compound of any one of embodiments 1-15, wherein X14 is x.

[0348] 17. The compound of any one of embodiments 1-15, wherein X14 is Y.

[0349] 18. The compound of any one of embodiments 1-17, wherein X15 is x.

[0350] 19. The compound of any one of embodiments 1-17, wherein X15 is Y.

[0351] 20. The compound of any one of embodiments 1-19, wherein X16 is x.WSGR Docket No. 65156-703.601

[0352] 21. The compound of any one of embodiments 1-19, wherein X16 is Y.

[0353] 22. The compound of any one of embodiments 1-21, wherein X19 is x.

[0354] 23. The compound of any one of embodiments 1-21, wherein X19 is Y.

[0355] 24. The compound of any one of embodiments 1-9, wherein X9 and X15 are each x.

[0356] 25. The compound of any one of embodiments 1-9, wherein X9, XI 5, and XI 8 are each x.

[0357] 26. The compound of any one of embodiments 1-7, wherein X8 and X13 are each Y.

[0358] 27. The compound of any one of embodiments 1-7, wherein X8, X13, and X16 are each Y.

[0359] 28. The compound of any one of embodiments 1-7, wherein X4 is Y, and X8 is x.

[0360] 29. The compound of embodiment 1, wherein X4 is Y, and X16 is x.

[0361] 30. The compound of embodiment 1, wherein X4 is Y, and X8 and X 16 are each x.

[0362] 31. The compound of any one of embodiments 1-5, wherein X5 and X13 are each x, and X8 is Y.

[0363] 32. The compound of any one of embodiments 1-5, wherein X5, X13, and X16 are each x, and X8 is Y.

[0364] 33. The compound of any one of embodiments 1-5, wherein X5 is Y, and X8 is x.

[0365] 34. The compound of any one of embodiments 1-5, wherein X5 is Y, and X13 is x.

[0366] 35. The compound of any one of embodiments 1-5, wherein X5 is Y, and X16 is x.

[0367] 36. The compound of any one of embodiments 1-5, wherein X5 is Y, and X8, XI 3, and X 16 are each x.

[0368] 37. The compound of any one of embodiments 1-36, wherein U1 is -Yx-(X3)(X4)-.

[0369] 38. The compound of any one of embodiments 1-36, wherein U1 is -x-(X3)(X4)-.

[0370] 39. The compound of any one of embodiments 1-36, wherein U1 is -(X3)(X4)-.

[0371] 40. The compound of any one of embodiments 1-36, wherein U1 is -(X4)-.

[0372] 41. The compound of embodiment 1, wherein U1 is absent.

[0373] 42. The compound of any one of embodiments 1-41, wherein U2 is -x-(X19)-.

[0374] 43. The compound of any one of embodiments 1-21, wherein U2 is -x-.

[0375] 44. The compound of any one of embodiments 1-21, wherein U2 is absent.

[0376] 45. The compound of embodiment 1, wherein Z is -(Ul)YxYxYYYxYxYxY(U2)-.

[0377] 46. The compound of embodiment 1 or 45, wherein Z is -YxYxYxYYYxYxYxY-.

[0378] 47. The compound of embodiment 1, 45, or 46, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 71.

[0379] 48. The compound of embodiment 1, wherein Z is -(Ul)YxYYxYYxYYxYY(U2)-.

[0380] 49. The compound of embodiment 1 or 48, wherein Z is -xY xYYxYYxYYxYYx-.

[0381] 50. The compound of embodiment 1, 48, or 49, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 72.

[0382] 51. The compound of embodiment 1 or 48, wherein Z is -YxYYxYYxYYxYYxx-.

[0383] 52. The compound of embodiment 1, 48, or 51, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 73.

[0384] 53. The compound of embodiment 1, wherein Z is -(Ul)YxYxxYYxYYxxY(U2)-.WSGR Docket No. 65156-703.601

[0385] 54. The compound of embodiment 1 or 53, wherein Z is -YxxYYxYxxYYxYYxxYx-.

[0386] 55. The compound of embodiment 1, 53, or 54, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 74.

[0387] 56. The compound of embodiment 1 or 53, wherein Z is -xxYYxY xxYYxYYxxYxY-.

[0388] 57. The compound of embodiment 1, 53, or 56, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 75.

[0389] 58. The compound of embodiment 1, wherein Z is -(Ul)xxYYxYYxxYxxY(U2)-.

[0390] 59. The compound of embodiment 1 or 58, wherein Z is -YxxYYxYYxxYxxYx-.

[0391] 60. The compound of embodiment 1, 58, or 59, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 76.

[0392] 61. The compound of embodiment 1, wherein Z is -(Ul)YxYxxYYxxYxxY(U2)-.

[0393] 62. The compound of embodiment 1 or 61, wherein Z is -YxYxxYYxxYxxYxY-.

[0394] 63. The compound of embodiment 1, 61, or 62, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 77.

[0395] 64. A compound of formula (Ila), or a pharmaceutically-acceptable salt or ionized form thereof:N-Terminus— Z— PNA 2-L 3— PEP 2— L 4 — C-Terminusmtira .j, wherein: '-Tcrminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andZ is -YY(x)mYY-, -[YYxxxx]t-, -(x)u(Y)kx(Y)k(x)u-, -YxYxxY(x)aYxYxx-, -[xYxxY]v-, -[Yxx]p-, - [YxxYxxxYxxx]n-, -[Yxxx]q-, -[YxxxYxx]rY-, -(Y)w(x)fYYY(x)j(Y)w-, -xYxYxxYxY-, - YxYYx-, -(x)bY(x)s, - xxYxxYxYxx-, -Yx(Yxx)bY-, -YxYxYxxYxxYxYx-, -xYxYYYxY-, - YxxYYxYY-, -YYxYYxxY-, or -YxxYYxxY-; wherein: each Y is independentlyeachWSGR Docket No. 65156-703.601 each R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralrhalis H; or each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH; each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPha2is H; or each R3is H and each RalPha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH; b, m, u, and q are each independently 4, 5, 6, 7, 8, or 9; s is 3, 4, 5, 6, 7, or 8; a and n are each independently 1, 2, or 3; w, r, v, and t are each independently is 2, 3, 4, or 5; k is 3, 4, or 5; each f and j is independently 4, 5, or 6; and p is 4, 5, 6, 7, 8, or 9.

[0396] 65. The compound of embodiment 64, wherein PNA1 is absent, or is a peptide nucleic acid sequence that is from 1 to 15 residues in length.

[0397] 66. The compound of embodiment 64 or 65, wherein each residue of the peptide nucleic acid sequence of PNA1 independently has a structure according to x or Y.

[0398] 67. The compound of any one of embodiments 64-66, wherein PNA2 is absent, or is a peptide nucleic acid sequence that is from 1 to 15 residues in length.

[0399] 68. The compound of any one of embodiments 64-67, wherein each residue of the peptide nucleic acid sequence of PNA2 independently has a structure according to x or Y.

[0400] 69. The compound of any one of embodiments 64-68, wherein Z is -YY(x)mYY-.

[0401] 70. The compound of any one of embodiments 64-69, wherein m is 4 or 5.

[0402] 71. The compound of any one of embodiments 64-70, wherein Z is -YYxxxxYY-.

[0403] 72. The compound of any one of embodiments 64-71, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 5.

[0404] 73. The compound of any one of embodiments 64-71, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 6.

[0405] 74. The compound of any one of embodiments 64-70, wherein Z is -YYxxxxxYY-.

[0406] 75. The compound of any one of embodiments 64-68 and 74, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 7.

[0407] 76. The compound of any one of embodiments 64-68, wherein Z is -[YYxxxx]t-.

[0408] 77. The compound of any one of embodiments 64-68 and 76, wherein t is 2.

[0409] 78. The compound of any one of embodiments 64-68, 76, and 77, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 5.

[0410] 79. The compound of any one of embodiments 64-68, 76, and 77, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 6.WSGR Docket No. 65156-703.601

[0411] 80. The compound of any one of embodiments 64-68, wherein Z is -(x)u(Y)kx(¥)k(x)u-.

[0412] 81. The compound of any one of embodiments 64-68 and 80, wherein each k is 3.

[0413] 82. The compound of any one of embodiments 64-68, 80, and 81, wherein u is 5, 6, 7.

[0414] 83. The compound of any one of embodiments 64-68 and 80-82, wherein Z is - (x)uYYYxYYY(x)u-.

[0415] 84. The compound of any one of embodiments 64-68 and 80-83, wherein Z is - xxxxxYYY xYYY xxxxx- .

[0416] 85. The compound of any one of embodiments 64-68 and 80-84, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 8.

[0417] 86. The compound of any one of embodiments 64-68 and 80-83, wherein Z is - xxxxxxYYY xYYY xxxxxx- .

[0418] 87. The compound of any one of embodiments 64-68, 80-83, and 86, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 9.

[0419] 88. The compound of any one of embodiments 64-68 and 80-83, wherein Z is - xxxxxxxYYY xYYY xxxxxxx- .

[0420] 89. The compound of any one of embodiments 64-68, 80-83, and 88, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 10.

[0421] 90. The compound of any one of embodiments 64-68, wherein Z is -YxYxxY(x)aYxYxx-.

[0422] 91. The compound of any one of embodiments 64-68 and 90, wherein Z is -YxYxxYxxYxYxx-.

[0423] 92. The compound of any one of embodiments 64-68, 64, 90, and 91, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 11.

[0424] 93. The compound of any one of embodiments 64-68 and 90, wherein Z is -YxYxxYxYxYxx-.

[0425] 94. The compound of any one of embodiments 64-68, 90, and 93, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 14.

[0426] 95. The compound of any one of embodiments 64-68, wherein Z is -[xYxxY]v-.

[0427] 96. The compound of any one of embodiments 64-68 and 95, wherein Z is -xYxxYxYxxY-.

[0428] 97. The compound of any one of embodiments 64-68, 95, and 96, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 12.

[0429] 98. The compound of any one of embodiments 64-68, 95, and 96, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 18.

[0430] 99. The compound of any one of embodiments 64-68, 95, and 96, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 45.

[0431] 100. The compound of any one of embodiments 64-68, 95, and 96, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 47.

[0432] 101. The compound of any one of embodiments 64-68, 95, and 96, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 51.

[0433] 102. The compound of any one of embodiments 64-68, wherein Z is -[Yxx]p-.

[0434] 103. The compound of any one of embodiments 64-68 and 102, wherein p is 4.WSGR Docket No. 65156-703.601

[0435] 104. The compound of any one of embodiments 64-68 and 102, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 72.

[0436] 105. The compound of any one of embodiments 64-68 and 102, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 73.

[0437] 106. The compound of any one of embodiments 64-68 and 102, wherein Z is -Y xxY xxY xxY xxY xx- .

[0438] 107. The compound of any one of embodiments 64-68, 102, and 106, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 55.

[0439] 108. The compound of any one of embodiments 64-68, 102, and 106, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 59.

[0440] 109. The compound of any one of embodiments 64-68 and 102, wherein Z is -Y xxY xxY xxY xxY xxY xx- .

[0441] 110. The compound of any one of embodiments 64-68, 102, and 109, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 14.

[0442] 111. The compound of any one of embodiments 64-68, 102, and 109, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 17.

[0443] 112. The compound of any one of embodiments 64-68, 102, and 109, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 20.

[0444] 113. The compound of any one of embodiments 64-68, 102, and 109, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 21.

[0445] 114. The compound of any one of embodiments 64-68 and 102, wherein Z is -Y xxY xxY xxY xxY xxY xxY xx- .

[0446] 115. The compound of any one of embodiments 64-68 and 102, wherein Z is -Y xxY xxY xxY xxY xxY xxY xxY xx- .

[0447] 116. The compound of any one of embodiments 64-68, 102, and 115, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 24.

[0448] 117. The compound of any one of embodiments 64-68, 102, 109, 114, and 115, wherein PNA1 is -Yxxx-.

[0449] 118. The compound of any one of embodiments 64-68, 102, 109, 114, and 115, wherein PNA1 is -Yx-.

[0450] 119. The compound of any one of embodiments 64-68, 102, 109, 114, and 115, wherein PNA1 is absent.

[0451] 120. The compound of any one of embodiments 64-68, 102, 109, 114, 115, and 117-119, wherein PNA2 is Y.

[0452] 121. The compound of any one of embodiments 64-68, 102, 109, 114, 115, and 117-119, wherein PNA2 is -Yx-.

[0453] 122. The compound of any one of embodiments 64-68, 102, 109, 114, 115, and 117-119, wherein PNA2 is -YxY-.WSGR Docket No. 65156-703.601

[0454] 123. The compound of any one of embodiments 64-68, 102, 109, 114, 115, and 117-119, whereinPNA2 is -Yxxx-.

[0455] 124. The compound of any one of embodiments 64-68, 102, 109, 114, 115, and 117-119, wherein PNA2 is -YxxxY-.

[0456] 125. The compound of any one of embodiments 64-68, 102, 109, 114, 115, and 117-119, wherein PNA2 is absent.

[0457] 126. The compound of any one of embodiments 64-68, wherein Z is -[YxxYxxxYxxx]n-.

[0458] 127. The compound of any one of embodiments 64-68 and 126, wherein Z is -YxxYxxxYxxx-.

[0459] 128. The compound of any one of embodiments 64-68, 126, and 127, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 43.

[0460] 129. The compound of any one of embodiments 64-68 and 126, wherein Z is -Y xxY xxxY xxxY xxY xxxY xxx- .

[0461] 130. The compound of any one of embodiments 64-68, 126, and 129, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 19.

[0462] 131. The compound of any one of embodiments 64-68, 126, 127, and 129, wherein PNA1 is absent.

[0463] 132. The compound of any one of embodiments 64-68, 126, 127, 129, and 131, wherein PNA2 is-YxxY-.

[0464] 133. The compound of any one of embodiments 64-68, 126, 127, 129, and 131, wherein PNA2 is Y.

[0465] 134. The compound of any one of embodiments 64-68, 126, 127, 129, and 131, wherein PNA2 is absent.

[0466] 135. The compound of any one of embodiments 64-68, wherein Z is -[Yxxx]q-.

[0467] 136. The compound of any one of embodiments 64-68 and 135, wherein Z is -Y xxxY xxxY xxxY xxxY xxxY xxx- .

[0468] 137. The compound of any one of embodiments 64-68, 135, and 136, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 22.

[0469] 138. The compound of any one of embodiments 64-68, 135, and 136, wherein PNA1 is absent.

[0470] 139. The compound of any one of embodiments 64-68, 135, 136, and 138, wherein PNA2 is Y.

[0471] 140. The compound of any one of embodiments 64-68, wherein Z is -[YxxxYxx]rY-.

[0472] 141. The compound of any one of embodiments 64-68 and 140, wherein Z is -Y xxxY xxY xxxY xxY - .

[0473] 142. The compound of any one of embodiments 64-68, 140, and 141, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 23.

[0474] 143. The compound of any one of embodiments 64-68, 140, and 141, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 16.

[0475] 144. The compound of any one of embodiments 64-68, 140, and 141, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 54.WSGR Docket No. 65156-703.601

[0476] 145. The compound of any one of embodiments 64-68, 140, and 141, wherein PNA1 is -Yxx-.

[0477] 146. The compound of any one of embodiments 64-68, 140, and 141, wherein PNA1 is absent.

[0478] 147. The compound of any one of embodiments 64-68, 140, 141, 145, and 146, wherein PNA2 is -xxYxxY-.

[0479] 148. The compound of any one of embodiments 64-68, 140, 141, 145, and 146, wherein PNA2 is -xxY xxY xxxY - .

[0480] 149. The compound of any one of embodiments 64-68, 140, 141, 145, and 146, wherein PNA2 is absent.

[0481] 150. The compound of any one of embodiments 64-68, wherein Z is -(Y)w(x)fYYY (x)j(Y)w-.

[0482] 151. The compound of any one of embodiments 64-68 and 150, wherein Z is YY(x)5YYY(x)6YY-

[0483] 152. The compound of any one of embodiments 64-68, 150, and 151, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 62.

[0484] 153. The compound of any one of embodiments 64-68, 150, and 151, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO: 62.

[0485] 154. The compound of any one of embodiments 64-68, 150, and 151, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 64.

[0486] 155. The compound of any one of embodiments 64-68, 150, and 151, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO: 64.

[0487] 156. The compound of any one of embodiments 64-68 and 150, wherein Z is YYY(X)4YYY(X)5YYY-.

[0488] 157. The compound of any one of embodiments 64-68, 150, and 156, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 63.

[0489] 158. The compound of any one of embodiments 64-68, 150, and 156, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO: 63.

[0490] 159. The compound of any one of embodiments 64-68 and 150, wherein Z is YY(x)4YYY(x)4YY-

[0491] 160. The compound of any one of embodiments 64-68, 150, and 159, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 49.

[0492] 161. The compound of any one of embodiments 64-68, 150, and 159, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO: 49.

[0493] 162. The compound of any one of embodiments 64-68, 150, and 159, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 50.

[0494] 163. The compound of any one of embodiments 64-68, 150, and 159, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO: 50.

[0495] 164. The compound of any one of embodiments 64-68, wherein Z is -xYxYxxYxY -.

[0496] 165. The compound of any one of embodiments 64-68 and 164, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 36.WSGR Docket No. 65156-703.601

[0497] 166. The compound of any one of embodiments 64-68 and 164, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 57.

[0498] 167. The compound of any one of embodiments 64-68 and 164, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 60.

[0499] 168. The compound of any one of embodiments 64-68, wherein Z is -YxYYx-.

[0500] 169. The compound of any one of embodiments 64-68 and 168, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 37.

[0501] 170. The compound of any one of embodiments 64-68 and 168, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 38.

[0502] 171. The compound of any one of embodiments 64-68 and 168, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 39.

[0503] 172. The compound of any one of embodiments 64-68 and 168, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 40.

[0504] 173. The compound of any one of embodiments 64-68 and 168, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 76.

[0505] 174. The compound of any one of embodiments 64-68 and 168, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 77.

[0506] 175. The compound of any one of embodiments 64-68, wherein Z is -(x)bY(x)s-.

[0507] 176. The compound of any one of embodiments 64-68 and 175, wherein Z is -(x)4Y(x)4-.

[0508] 177. The compound of any one of embodiments 64-68, 175, and 176, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 48.

[0509] 178. The compound of any one of embodiments 64-68 and 175, wherein Z is -(x)4Y(x)s-.

[0510] 179. The compound of any one of embodiments 64-68 and 175, wherein Z is -(x)4Y(x)v-.

[0511] 180. The compound of any one of embodiments 64-68, 175, and 179, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 58.

[0512] 181. The compound of any one of embodiments 64-68 and 175, wherein Z is -(x)4Y(x)5-.

[0513] 182. The compound of any one of embodiments 64-68 and 175, wherein Z is -(x)4Y(x)e-.

[0514] 183. The compound of any one of embodiments 64-68 and 175, wherein Z is -(x)4Y(x)v-.

[0515] 184. The compound of any one of embodiments 64-68, 175, and 183, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 61.

[0516] 185. The compound of any one of embodiments 64-68, 175, 176, 178, 179, and 181-183, wherein PNA1 is -YxYx-.

[0517] 186. The compound of any one of embodiments 64-68, 175, 176, 178, 179, and 181-183, wherein PNA1 is -YxxY-.

[0518] 187. The compound of any one of embodiments 64-68, 175, 176, 178, 179, and 181-183, wherein PNA 1 is absent.

[0519] 188. The compound of any one of embodiments 64-68, 175, 176, 178, 179, and 181-183, wherein PNA2 is -YxYx-.WSGR Docket No. 65156-703.601

[0520] 189. The compound of any one of embodiments 64-68, 175, 176, 178, 179, 181-183, and 185- 188, wherein PNA2 is -YxxY-.

[0521] 190. The compound of any one of embodiments 64-68, 175, 176, 178, 179, 181-183, and 185- 188, wherein is absent.

[0522] 191. The compound of any one of embodiments 64-68, wherein Z is -xxYxxYxY xx-.

[0523] 192. The compound of any one of embodiments 64-68 and 191, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 35.

[0524] 193. The compound of any one of embodiments 64-68 and 191, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 44.

[0525] 194. The compound of any one of embodiments 64-68 and 191, wherein PNA1 is Y.

[0526] 195. The compound of any one of embodiments 64-68 and 191, wherein PNA1 is absent.

[0527] 196. The compound of any one of embodiments 64-68, 191, 194, and 195, wherein PNA2 is Y.

[0528] 197. The compound of any one of embodiments 64-68, 191, 194, and 195, wherein PNA2 is - YxxY-.

[0529] 198. The compound of any one of embodiments 64-68, 191, 194, and 195, wherein PNA2 is absent.

[0530] 199. The compound of any one of embodiments 64-68, wherein Z is -Yx(Yxx)bY-.

[0531] 200. The compound of any one of embodiments 64-68 and 199, wherein Z is -Yx(Yxx)4Y-.

[0532] 201. The compound of any one of embodiments 64-68, 199, and 200, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 52.

[0533] 202. The compound of any one of embodiments 64-68, 199, and 200, wherein PNA1 is absent.

[0534] 203. The compound of any one of embodiments 64-68, 199, 200, and 202, wherein PNA2 is -xY-.

[0535] 204. The compound of any one of embodiments 64-68, 199, 200, and 202, wherein PNA2 is absent.

[0536] 205. The compound of any one of embodiments 64-68, wherein Z is -YxYxYxxYxxYxYx-.

[0537] 206. The compound of any one of embodiments 64-68 and 205, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 56.

[0538] 207. The compound of any one of embodiments 64-68 and 205, wherein PNA1 is absent.

[0539] 208. The compound of any one of embodiments 64-68, 205, and 207, wherein PNA2 is -YxxY-.

[0540] 209. The compound of any one of embodiments 64-68, 205, and 207, wherein PNA2 is absent.

[0541] 210. The compound of any one of embodiments 64-68, wherein Z is -xYxYYYxY-.

[0542] 211. The compound of any one of embodiments 64-68 and 210, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 71.

[0543] 212. The compound of any one of embodiments 64-68 and 210, wherein PNA1 is -YxY-.

[0544] 213. The compound of any one of embodiments 64-68 and 210, wherein PNA1 is absent.

[0545] 214. The compound of any one of embodiments 64-68, 210, 212, and 213, wherein PNA2 is - xYxY-.WSGR Docket No. 65156-703.601

[0546] 215. The compound of any one of embodiments 64-68, 210, 212, and 213, wherein PNA2 is absent.

[0547] 216. The compound of any one of embodiments 64-68, wherein Z is -YxxYYxYY-.

[0548] 217. The compound of any one of embodiments 64-68 and 216, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 74.

[0549] 218. The compound of any one of embodiments 64-68 and 216, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 75.

[0550] 219. The compound of any one of embodiments 64-68 and 216, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 76.

[0551] 220. The compound of any one of embodiments 64-68 and 216, wherein PNA1 is -xxYYx-.

[0552] 221. The compound of any one of embodiments 64-68 and 216, wherein PNA1 is -YxxYYx-.

[0553] 222. The compound of any one of embodiments 64-68 and 216, wherein PNA1 is absent.

[0554] 223. The compound of any one of embodiments 64-68, 216, 221, and 222, wherein PNA2 is - xxYx-.

[0555] 224. The compound of any one of embodiments 64-68, 216, 221, and 222, wherein PNA2 is - xxYxY-.

[0556] 225. The compound of any one of embodiments 64-68, 216, 221, and 222, wherein PNA2 is absent.

[0557] 226. The compound of any one of embodiments 64-68, wherein Z is -YYxYYxxY-.

[0558] 227. The compound of any one of embodiments 64-68 and 226, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 74.

[0559] 228. The compound of any one of embodiments 64-68 and 226, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 75.

[0560] 229. The compound of any one of embodiments 64-68 and 226, wherein PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 76.

[0561] 230. The compound of any one of embodiments 64-68 and 226, wherein PNA1 is -Yxx-.

[0562] 231. The compound of any one of embodiments 64-68 and 226, wherein PNA1 is absent.

[0563] 232. The compound of any one of embodiments 64-68, 226, 230, and 231, wherein PNA2 is - xxYx-.

[0564] 233. The compound of any one of embodiments 64-68, 226, 230, and 231, wherein PNA2 is - xxYxY-.

[0565] 234. The compound of any one of embodiments 64-68, 226, 230, and 231, wherein PNA2 is absent.

[0566] 235. The compound of any one of embodiments 64-68, wherein Z is -YxxYYxxY-.

[0567] 236. The compound of any one of embodiments 64-68 and 235, wherein -PNA1-Z-PNA2- is a peptide nucleic acid sequence according to SEQ ID NO: 77.

[0568] 237. The compound of any one of embodiments 64-68 and 235, wherein PNA1 is -Yx-.

[0569] 238. The compound of any one of embodiments 64-68 and 235, wherein PNA1 is absent.WSGR Docket No. 65156-703.601

[0570] 239. The compound of any one of embodiments 64-68, 235, 237, and 238, wherein PNA2 is - xxYx-.

[0571] 240. The compound of any one of embodiments 64-68, 235, 237, and 238, wherein PNA2 is - xxYxY-.

[0572] 241. The compound of any one of embodiments 64-68, 235, 237, and 238, wherein PNA2 is absent.

[0573] 242. A compound according to formula (VII), or a pharmaceutically-acceptable salt or ionized form thereof:us(VII)wherein:A-Terminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent;Z is a peptide nucleic acid sequence, wherein each residue of Z independently has a structure according to x or Y, wherein:each R2is independently methyl substituted with a nucleobase that is not guanine; each R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH.

[0574] 243. The compound of embodiments 1 or 242, wherein each R2 is independently methyl substituted with a nucleobase selected from cytosine and thymine.WSGR Docket No. 65156-703.601

[0575] 244. The compound of any one of embodiments 1, 242, and 243, wherein each R4 is independently methyl substituted with a nucleobase.

[0576] 245. The compound of any one of embodiments 1 and 242-244, wherein each R4 is independently methyl substituted with cytosine, adenine, or guanine.

[0577] 246. The compound of any one of embodiments 1 and 242-244, wherein each R4 is independently methyl substituted with cytosine, thymine, or guanine.

[0578] 247. The compound of any one of embodiments 242-246, wherein at least about 20% of the residues of Z have a structure according to Y.

[0579] 248. The compound of any one of embodiments 242-246, wherein from about 40% to about 80% of the residues of Z have a structure according to Y.

[0580] 249. The compound of any one of embodiments 242-246, wherein no more than about 80% of the residues of Z have a structure according to Y.

[0581] 250. The compound of any one of embodiments 242-249, wherein Z is from 10 to 30 residues in length.

[0582] 251. The compound of any one of embodiments 242-249, wherein Z is from 10 to 20 residues in length, wherein 7, 8, or 9 of the residues of Z have a structure according to Y.

[0583] 252. The compound of any one of embodiments 242-249, wherein 5, 6, 7, 8, 9, or 10 of the residues of Z have a structure according to Y.

[0584] 253. The compound of any one of embodiments 242-246, wherein Z is -xYxYYxYYxYYxYYx-.

[0585] 254. The compound of any one of embodiments 242-246, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 72.

[0586] 255. The compound of any one of embodiments 242-246, wherein Z is -YxYYxYYxYYxYYxx-.

[0587] 256. The compound of any one of embodiments 242-246, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 73.

[0588] 257. The compound of any one of embodiments 242-246, wherein Z is - YxxYYxYxxYYxYYxxYx-.

[0589] 258. The compound of any one of embodiments 242-246, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 74.

[0590] 259. The compound of any one of embodiments 242-246, wherein Z is - xxYYxYxxYYxYYxxYxY-.

[0591] 260. The compound of any one of embodiments 242-246, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 75.

[0592] 261. The compound of any one of embodiments 242-246, wherein Z is -YxxYYxYYxxYxxYx-.

[0593] 262. The compound of any one of embodiments 242-246, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 76.

[0594] 263. The compound of any one of embodiments 242-246, wherein Z is -YxYxxYYxxYxxYxY-.

[0595] 264. The compound of any one of embodiments 242-246, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 77.WSGR Docket No. 65156-703.601

[0596] 265. A compound of formula (V), or a pharmaceutically-acceptable salt or ionized form thereof:N-Terminus“ Z— PNA 2-L 3— PEP 2— L 4 — C-Terminus wherein:N-Terminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA 1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andZ is a peptide nucleic acid sequence.

[0597] 266. The compound of embodiment 265, wherein Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-77.

[0598] 267. The compound of embodiment 265, wherein Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 3-24.

[0599] 268. The compound of embodiment 265, wherein Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 25-34.

[0600] 269. The compound of embodiment 265, wherein Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 35-64.

[0601] 270. The compound of embodiment 265, wherein Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 65-70.

[0602] 271. The compound of embodiment 265, wherein Z is a peptide nucleic acid sequence according to any one of SEQ ID NOs 71-77.

[0603] 272. The compound of embodiment 265, wherein each residue of the peptide nucleic acid sequence has a structure that is independently Y or x, wherein: each Y is independentlyeach x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; andWSGR Docket No. 65156-703.601 each R3is H and each RalPha2is hydroxyalkyl; or each R3is hydroxyalkyl and each RalPha2is H; or each R3and each RalPha2is H.

[0604] 273. The compound of embodiment 272, wherein R3is hydroxyalkyl and each RalPha2is H.

[0605] 274. The compound of embodiment 272, wherein each R3and RalPha2is H.

[0606] 275. The compound of any one of embodiments 1-265, and 272-274, wherein each Y is independently

[0607] 276. The compound of any one of embodiments 1-265, and 272-275, wherein each x is independently

[0608] 277. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R2is independently methyl substituted with a nucleobase.

[0609] 278. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-241, and 277, wherein each R4is independently methyl substituted with a nucleobase.

[0610] 279. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R2is independently methyl substituted with cytosine, adenine, or guanine.

[0611] 280. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R2is independently methyl substituted with cytosine, thymine, or guanine.

[0612] 281. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R4is independently methyl substituted with cytosine, adenine, or guanine.WSGR Docket No. 65156-703.601

[0613] 282. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R4is independently methyl substituted with cytosine, thymine, or guanine.

[0614] 283. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R2is independently methyl substituted with a nucleobase that is not guanine.

[0615] 284. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, and 237-241, wherein each R2is independently methyl substituted with a cytosine or thymine.

[0616] 285. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, and 265, wherein the nucleobases of R2and R4together form at least one cytosine-thymine-guanine sequence.

[0617] 286. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, 265, and 285 wherein each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous thymine -containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue.

[0618] 287. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, 265, and 286 wherein each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous guanine -containing peptide nucleic acid residue is a thymine-containing peptide nucleic acid residue.

[0619] 288. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, 265, 286, and 287, wherein each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous cytosine-containing peptide nucleic acid residue is a guanine-containing peptide nucleic acid residue.WSGR Docket No. 65156-703.601

[0620] 289. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, and 265, wherein the nucleobases of R2and R4together form at least one cytosine-adenine-guanine sequence.

[0621] 290. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, 265, and 289, wherein each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous adenine-containing peptide nucleic acid residue is a cytosine-containing peptide nucleic acid residue.

[0622] 291. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, 265, 289, and 290, wherein each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous guanine-containing peptide nucleic acid residue is an adenine-containing peptide nucleic acid residue.

[0623] 292. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-242, 265, 289, 290, and 291, wherein each peptide nucleic acid residue that is bound via its C-terminus to an N-terminus of a contiguous cytosine-containing peptide nucleic acid residue is a guanine -containing peptide nucleic acid residue.

[0624] 293. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each RalPhalis H.

[0625] 294. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein R1is independently guanidinoalkyl, and each RalPhalis H.

[0626] 295. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207-WSGR Docket No. 65156-703.601210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is independently guanidino-Ci-4alkyl, and each Ralphalis H.

[0627] 296. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl, and each Ralphalis H.

[0628] 297. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is independently 4-guanidinobut-l-yl, and each Ralphalis H.

[0629] 298. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is independently 3-guanidinoprop-l-yl and each Ralphalis H.

[0630] 299. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is H and each RalPhalis independently alkyl substituted with a group that bears a positive charge at physiological pH.

[0631] 300. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is H and each RalPhalis independently guanidinoalkyl.

[0632] 301. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is H and each RalPhalis independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl.

[0633] 302. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is H and each RalPhalis independently 3-guanidinoprop-l-yl.WSGR Docket No. 65156-703.601

[0634] 303. The compound of any one of embodiments 1-46, 48, 49, 51, 53, 54, 56, 58, 59, 61, 62, 64-71, 74, 76, 77, 80, 83, 84, 86, 88, 90, 91, 93, 95, 96, 102, 106, 109, 114, 115, 117-127, 129, 131-136, 138- 141, 145-151, 156, 159, 161, 164, 168, 175, 176, 178, 179, 181-183, 185-191, 194-200, 202-205, 207- 210, 212-216, 220-226, 230-235, 237-253, 255, 257, 259, 261, 263, and 265, wherein each R1is H and each RalPhalis independently 4-guanidinobut-l-yl.

[0635] 304. The compound of any one of embodiments 1-265 and 272-303, wherein each R2and R4is independently methyl substituted with a nucleobase.

[0636] 305. The compound of embodiment 304, wherein the nucleobases of R2and R4together form a sequence of nucleobases that binds a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0637] 306. The compound of embodiment 304 or 305, wherein the nucleobases of R2and R4together form a sequence of nucleobases that has at least 80% complementarity to a target sequence of equal length within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0638] 307. The compound of any one of embodiments 304-306, wherein the nucleobases of R2and R4together form a sequence of nucleobases that is complementary to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0639] 308. The compound of any one of embodiments 304-306, wherein each nucleobase together forms a sequence of nucleobases that has at least 80% identity to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

[0640] 309. The compound of any one of embodiments 305-308, wherein the target sequence consists of contiguous repeats of CAG, CTG, or CUG.

[0641] 310. The compound of any one of embodiments 305-308, wherein the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CAG, CTG, or CUG.

[0642] 311. The compound of any one of embodiments 305-310, wherein the expanded repeat region is causative of a polyglutamine disease.

[0643] 312. The compound of embodiment 311, wherein the polyglutamine disease is Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, or spinocerebellar ataxia type 17.

[0644] 313. The compound of embodiment 311, wherein the polyglutamine disease is Huntington’s disease.

[0645] 314. The compound of any one of embodiments 305-310, wherein the repeat expansion disease is myotonic dystrophy type 1.

[0646] 315. The compound of any one of embodiments 305-310, wherein the repeat expansion disease is spinocerebellar ataxia type 8.

[0647] 316. The compound of any one of embodiments 305-310, wherein the repeat expansion disease is Huntington's disease-like 2 (HDL2).WSGR Docket No. 65156-703.601

[0648] 317. The compound of any one of embodiments 305-310, wherein the repeat expansion disease is Fuchs comeal dystrophy.

[0649] 318. The compound of any one of embodiments 304-317, wherein the target sequence is DNA.

[0650] 319. The compound of any one of embodiments 304-317, wherein the target sequence is RNA.

[0651] 320. The compound of any one of embodiments 1-319, wherein PEP1 is a peptide sequence.

[0652] 321. The compound of any one of embodiments 1-319, wherein PEP l is a peptide sequence that is from 1 to 10 residues in length.

[0653] 322. The compound of any one of embodiments 1-319, wherein PEP1 is a peptide sequence that is from 1 to 5 residues in length.

[0654] 323. The compound of any one of embodiments 1-321, wherein each residue of PEP 1 comprises a side chain that is positively charged at physiological pH.

[0655] 324. The compound of any one of embodiments 1-321, wherein PEP1 is D-Lys.

[0656] 325. The compound of any one of embodiments 1-321, wherein PEP1 is D-Arg.

[0657] 326. The compound of any one of embodiments 1-321, wherein PEP1 is D-A...

Claims

WSGR Docket No. 65156-703.601CLAIMSWhat is claimed is:

1. A compound of formula (VI), or a pharmaceutically-acceptable salt or ionized form thereof:us(VI)wherein: '-Tcrminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent;- Z is -(Ul)(X5)-xY-(X8)(X9)-YYx-(X13)(X14)(X15)(X16)-Y-(U2)-;- U1 is -Yx-(X3)(X4)-, -x-(X3)(X4)-, -(X3)(X4)-, -(X4)-, or absent;U2 is -x-(X19)-, -x-, or absent;- each of X3, X4, X5, X8, X9, XI 2, XI 3, XI 4, XI 5, XI 6, and X19 is independently Y or x; / < °^r2\II HRI o H2| H ° II \ N“H“C -N-j-0 / *" each Y is independently paiphai . each x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; and each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH.

2. The compound of claim 1, wherein X9 and X15 are each x.

3. The compound of claim 1, wherein X9, XI 5, and X18 are each x.

4. The compound of claim 1, wherein X8 and X13 are each Y.

5. The compound of claim 1, wherein X8, X13, and X16 are each Y.

6. The compound of claim 1, wherein X4 is Y, and X8 is x.WSGR Docket No. 65156-703.6017. The compound of claim 1, wherein X4 is Y, and X16 is x.

8. The compound of claim 1, wherein X4 is Y, and X8 and X16 are each x.

9. The compound of claim 1, wherein X5 and X13 are each x, and X8 is Y.

10. The compound of claim 1, wherein X5, XI 3, and X16 are each x, and X8 is Y.

11. The compound of claim 1, wherein X5 is Y, and X8 is x.

12. The compound of claim 1, wherein X5 is Y, and X13 is x.

13. The compound of claim 1, wherein X5 is Y, and X16 is x.

14. The compound of claim 1, wherein X5 is Y, and X8, X13, and X16 are each x.

15. The compound of any one of claims 1-14, wherein U1 is -Yx-(X3)(X4)-.

16. The compound of any one of claims 1-14, wherein U1 is -x-(X3)(X4)-.

17. The compound of any one of claims 1-14, wherein U1 is -(X3)(X4)-.

18. The compound of any one of claims 1-14, wherein U1 is -(X4)-.

19. The compound of claim 1, wherein U1 is absent.

20. The compound of any one of claims 1-19, wherein U2 is -x-(X19)-.

21. The compound of any one of claims 1-19, wherein U2 is -x-.

22. The compound of any one of claims 1-19, wherein U2 is absent.

23. The compound of claim 1, wherein Z is -(Ul)YxYxYYYxYxYxY(U2)-.

24. The compound of claim 1 or 23, wherein Z is -YxYxYxYYYxYxYxY-.

25. The compound of claim 1, 23, or 24, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 71.

26. The compound of claim 1, wherein Z is -(Ul)YxYYxYYxYYxYY(U2)-.

27. The compound of claim 1 or 26, wherein Z is -xYxYYxYYxYYxYYx-.

28. The compound of claim 1, 26, or 27, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 72.

29. The compound of claim 1 or 26, wherein Z is -YxYYxYYxYYxYYxx-.

30. The compound of claim 1, 26, or 29, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 73.

31. The compound of claim 1, wherein Z is -(Ul)YxYxxYYxYYxxY(U2)-.

32. The compound of claim 1 or 31, wherein Z is -YxxYYxYxxYYxYYxxYx-.

33. The compound of claim 1, 31, or 32, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 74.

34. The compound of claim 1 or 31, wherein Z is -xxYYxYxxYYxYYxxYxY-.

35. The compound of claim 1, 31, or 34, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 75.

36. The compound of claim 1, wherein Z is -(Ul)xxYYxYYxxYxxY(U2)-.

37. The compound of claim 1 or 36, wherein Z is -YxxYYxYYxxYxxYx-.

38. The compound of claim 1, 36, or 37, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 76.WSGR Docket No. 65156-703.60139. The compound of claim 1, wherein Z is -(U 1)YXYXXYY xxYxxY(U2)-.

40. The compound of claim 1 or 39, wherein Z is -YxYxxYYxxYxxYxY-.

41. The compound of claim 1, 39, or 40, wherein Z is a peptide nucleic acid sequence according to SEQ ID NO 77.

42. The compound of any one of claims 1-41, wherein each Y is independently43. The compound of any one of claims 1-42, wherein each x is independently44. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, and 40, wherein each R2is independently methyl substituted with a nucleobase.

45. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44, wherein each R4is independently methyl substituted with a nucleobase.

46. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, and 40, wherein each R2is independently methyl substituted with cytosine, adenine, or guanine.

47. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, and 40, wherein each R2is independently methyl substituted with cytosine, thymine, or guanine.

48. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 46, wherein each R4is independently methyl substituted with cytosine, adenine, or guanine.

49. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 47, wherein each R4is independently methyl substituted with cytosine, thymine, or guanine.

50. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, and 40, wherein each R2is independently methyl substituted with a nucleobase that is not guanine.

51. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 50, wherein each R2is independently methyl substituted with a cytosine or thymine.

52. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, 47, and 49, wherein the nucleobases of R2and R4together form at least one cytosine-thymine-guanine sequence.

53. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, 46, and 48, wherein the nucleobases of R2and R4together form at least one cytosine-adenine-guanine sequence.

54. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44-53, wherein each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralrhalis H.

55. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44-53, wherein R1is independently guanidinoalkyl, and each RalPhalis H.WSGR Docket No. 65156-703.60156. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44-53, wherein each R1is independently guanidino-Ci-4alkyl, and each Ralphalis H.

57. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44-53, wherein each R1is independently 3-guanidinoprop-l-yl or 4-guanidinobut-l-yl, and each Ralphalis H.

58. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44-53, wherein each R1is independently 4-guanidinobut-l-yl, and each Ralrhalis H.

59. The compound of any one of claims 1-24, 26, 27, 29, 31, 32, 34, 36, 37, 39, 40, and 44-53, wherein each R1is independently 3-guanidinoprop-l-yl and each RalPhalis H.

60. The compound of any one of claims 1-59, wherein each R2and R4is independently methyl substituted with a nucleobase.

61. The compound of claim 60, wherein the nucleobases of R2and R4together form a sequence of nucleobases that binds a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

62. The compound of claim 60 or 61, wherein the nucleobases of R2and R4together form a sequence of nucleobases that has at least 80% complementarity to a target sequence of equal length within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

63. The compound of any one of claims 60-62, wherein the nucleobases of R2and R4together form a sequence of nucleobases that is complementary to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

64. The compound of any one of claims 60-62, wherein each nucleobase together forms a sequence of nucleobases that has at least 80% identity to a target sequence within an expanded repeat region, wherein the expanded repeat region is causative of a repeat expansion disease.

65. The compound of any one of claims 61-64, wherein the target sequence consists of contiguous repeats of CAG, CTG, or CUG.

66. The compound of any one of claims 61-64, wherein the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CAG, CTG, or CUG.

67. The compound of any one of claims 61-66, wherein the expanded repeat region is causative of a polyglutamine disease.

68. The compound of claim 67, wherein the polyglutamine disease is Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, or spinocerebellar ataxia type 17.

69. The compound of claim 67, wherein the polyglutamine disease is Huntington’s disease.

70. The compound of any one of claims 61-66, wherein the repeat expansion disease is myotonic dystrophy type 1.

71. The compound of any one of claims 61-66, wherein the repeat expansion disease is spinocerebellar ataxia type 8.WSGR Docket No. 65156-703.60172. The compound of any one of claims 61-66, wherein the repeat expansion disease is Huntington's disease-like 2 (HDL2).

73. The compound of any one of claims 61-66, wherein the repeat expansion disease is Fuchs comeal dystrophy.

74. The compound of any one of claims 60-73, wherein the target sequence is DNA.

75. The compound of any one of claims 60-73, wherein the target sequence is RNA.

76. The compound of any one of claims 1-75, wherein PEP1 is a peptide sequence.

77. The compound of any one of claims 1-75, wherein PEP1 is a peptide sequence that is from 1 to 10 residues in length.

78. The compound of any one of claims 1-75, wherein PEP1 is a peptide sequence that is from 1 to 5 residues in length.

79. The compound of any one of claims 1-77, wherein each residue of PEP1 comprises a side chain that is positively charged at physiological pH.

80. The compound of any one of claims 1-77, wherein PEP1 is D-Lys.

81. The compound of any one of claims 1-77, wherein PEP1 is D-Arg.

82. The compound of any one of claims 1-77, wherein PEP1 is D-Arg-D-Arg.

83. The compound of any one of claims 1-43, wherein PEP1 is absent.

84. The compound of any one of claims 1-83, wherein PEP2 is a peptide sequence.

85. The compound of any one of claims 1-83, wherein PEP2 is a peptide sequence that is from 1 to 10 residues in length.

86. The compound of any one of claims 1-83, wherein PEP2 is a peptide sequence that is from 1 to 5 residues in length.

87. The compound of any one of claims 1-85, wherein each residue of PEP2 comprises a side chain that is positively charged at physiological pH.

88. The compound of any one of claims 1-87, wherein PEP2 is D-Lys.

89. The compound of any one of claims 1-87, wherein PEP2 is D-Arg.

90. The compound of any one of claims 1-87, wherein PEP1 is D-Arg-D-Arg.

91. The compound of any one of claims 1-83, wherein PEP2 is absent.

92. The compound of any one of claims 1-91, wherein N-terminus is H.

93. The compound of any one of claims 1-91, wherein N-terminus is acyl.

94. The compound of any one of claims 1-91, wherein N-terminus is Ci-4acyl.

95. The compound of any one of claims 1-91, wherein N-terminus is acetyl.

96. The compound of any one of claims 1-91, wherein N-terminus is a fluorophore.

97. The compound of any one of claims 1-91, wherein N-terminus is a biologically active compound.

98. The compound of claim 97, wherein the biologically active compound is therapeutically-active.

99. The compound of claim 97, wherein the biologically active compound is diagnostically active.

100. The compound of claim 97, wherein the biologically active compound is an oligonucleotide or a targeted small molecule inhibitor or activator.WSGR Docket No. 65156-703.601101. The compound of any one of claims 1-100, wherein C-terminus is -O-alkyl.

102. The compound of any one of claims 1-100, wherein C-terminus is -O-Ci-ealkyl.

103. The compound of any one of claims 1-100, wherein C-terminus is -OMe.

104. The compound of any one of claims 1-100, wherein C-terminus is -OEt.

105. The compound of any one of claims 1-100, wherein C-terminus is -NH2.

106. The compound of any one of claims 1-100, wherein C-terminus is a fluorophore.

107. The compound of any one of claims 1-100, wherein C-terminus is a biologically active compound.

108. The compound of claim 107, wherein the biologically active compound is therapeutically-active.

109. The compound of claim 107, wherein the biologically active compound is diagnostically active.

110. The compound of claim 107, wherein the biologically active compound is an oligonucleotide or a targeted small molecule inhibitor or activator.

111. The compound of any one of claims 1-75, wherein PEP1 is absent, and N-Terminus is acyl.

112. The compound of any one of claims 1-75, wherein PEP1 is absent, and N-Terminus is Ci-4acyl.

113. The compound of any one of claims 1-75, wherein PEP1 is absent, and N-Terminus is acetyl.

114. The compound of any one of claims 1-75, wherein PEP1 and PEP2 are each absent, and N-Terminus is acyl.

115. The compound of any one of claims 1-75, wherein PEP1 and PEP2 are each absent, and N- Terminus is Ci-4acyl.

116. The compound of any one of claims 1-75, wherein PEP1 and PEP2 are each absent, and N- Terminus is acetyl.

117. The compound of any one of claims 1-116, wherein LI is the linker group.

118. The compound of any one of claims 1-117, wherein L2 is the linker group.

119. The compound of any one of claims 1-118, wherein L3 is the linker group.

120. The compound of any one of claims 1-119, wherein L4 is the linker group.

121. The compound of any one of claims 117-120, wherein the linker group is cleavable.

122. The compound of any one of claims 117-120, wherein the linker group is non-cleavable.

123. The compound of any one of claims 117-120, wherein the linker group is a peptide sequence.

124. The compound of any one of claims 117-120, wherein the linker group is a polyamine sequence.

125. The compound of any one of claims 117-120, wherein the linker group is a polyamide sequence.

126. The compound of any one of claims 117-120, wherein the linker group comprises polyethylene glycol.

127. The compound of any one of claims 117-120, wherein the linker is cleavable by physiological conditions.

128. The compound of any one of claims 1-116, wherein LI is absent.

129. The compound of any one of claims 1-116 and 128, wherein L2 is absent.

130. The compound of any one of claims 1-116, 128, and 129, wherein L3 is absent.

131. The compound of any one of claims 1-116, and 128-130, wherein L4 is absent.

132. A compound of formula (Ila), or a pharmaceutically-acceptable salt or ionized form thereof:WSGR Docket No. 65156-703.601N-Terminus L 1 — PEP 1— L 2 PNA — Z— PNA 2-L 3— PEP 2— L 4 — C-Terminuswherein: '-Tcrminus is H, acyl, a fluorophore, a biologically active compound, or a peptide sequence;C-Terminus is OH, O-alkyl, a fluorophore, a biologically active compound, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; and- Z is -YY(x)mYY-, -[YYxxxx]t-, -(x)u(Y)kx(Y)k(x)u-, -YxYxxY(x)aYxYxx-, -[xYxxY]v-, -[Yxx]p-, -[YxxYxxxYxxx]n-, -[Yxxx]q-, -[YxxxYxx]rY-, -(Y)w(x)YYY(x)j(Y)w-, -xYxYxxYxY-, - YxYYx-, -(x)bY(x)s, - xxYxxYxYxx-, -Yx(Yxx)bY-, -YxYxYxxYxxYxYx-, -xYxYYYxY-, - YxxYYxYY-, -YYxYYxxY-, or -YxxYYxxY-; wherein: each Y is independentlyeach x is independentlyeach R2and R4is independently methyl substituted with a heterocycle; each R1is independently alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralphalis H; or each R1is H and each Ralphalis independently alkyl substituted with a group that bears a positive charge at physiological pH; each R3is independently not alkyl substituted with a group that bears a positive charge at physiological pH, and each Ralpha2is H; or each R3is H and each Ralpha2is independently not alkyl substituted with a group that bears a positive charge at physiological pH; b, m, u, and q are each independently 4, 5, 6, 7, 8, or 9; s is 3, 4, 5, 6, 7, or 8; a and n are each independently 1, 2, or 3; w, r, v, and t are each independently is 2, 3, 4, or 5; k is 3, 4, or 5; each f and j is independently 4, 5, or 6; and p is 4, 5, 6, 7, 8, or 9.

133. A compound of formula (IV), or a pharmaceutically-acceptable salt or ionized form thereof:WSGR Docket No. 65156-703.601N-Terminus - L 1 — PEP 1— L 2 - PNA t --Terminus (IV) wherein:JV-Terminus is H, acyl, or a peptide sequence;C-Terminus is OH, O-alkyl, a peptide sequence, or NH2; each of PEP 1 and PEP2 is independently a peptide sequence or absent; each of PNA1 and PNA2 is independently a peptide nucleic acid sequence or absent; each of LI, L2, L3, and L4 is independently a linker group or absent; andwherein: each RNis independently methyl substituted with a heterocycle; each RGis independently alkyl substituted with a group that bears a positive charge at physiological pH or hydroxyalkyl, and each Ralphais H; or each RGis H and each Ralphais independently alkyl substituted with a group that bears a positive charge at physiological pH or hydroxyalkyl; and the number of units with variables defined independently is at least 10, wherein in 40-60% of the units with variables defined independently, either: (a) each RGis independently hydroxyalkyl and each Ralphais H, or (b) each RGis H and each Ralphais independently hydroxyalkyl; and in the remainder of the units with variables defined independently, either: (a) each RGis independently a group that bears a positive charge at physiological pH and Ralrhais H, or (b) each RGis H and each RalPhais independently a group that bears a positive charge at physiological pH.

134. A pharmaceutical composition comprising a compound of any one of claims 1-133 and at least one pharmaceutically-acceptable carrier or excipient.

135. The pharmaceutical composition of claim 134, further comprising an anti-aggregation agent.

136. The pharmaceutical composition of claim 135, wherein the anti -aggregation agent is a sugar.

137. The pharmaceutical composition of claim 136, wherein the sugar is dextrose.

138. The pharmaceutical composition of any one of claims 134-137, further comprising an amino acid.

139. The pharmaceutical composition of claim 138, wherein the amino acid comprises a side chain that is charged at physiological pH.

140. The pharmaceutical composition of claim 138, wherein the amino acid is histidine.

141. The pharmaceutical composition of claim 138, wherein the amino acid is L-histidine.WSGR Docket No. 65156-703.601142. A method of treating a condition in a subject, comprising administering to the subject a therapeutically-effective amount of a compound of any one of claims 1-133 or a pharmaceutical composition of any one of claims 134-141.

143. The method of claim 142, wherein comprising administering the compound by subcutaneous administration.

144. The method of claim 142, wherein comprising administering the compound by intramuscular administration.

145. The method of claim 142, wherein comprising administering the compound by intracerebroventricular administration.

146. The method of claim 142, wherein comprising administering the compound by oral administration.

147. The method of claim 142, wherein comprising administering the compound by intrathecal administration.

148. The method of any one of claims 142-147, wherein the repeat expansion disease is associated with a repeat expansion comprising contiguous repeats of CAG, CTG, or CUG.

149. The method of claim 148, wherein the expanded repeat region is causative of a polyglutamine disease.

150. The method of claim 149, wherein the polyglutamine disease is Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, or spinocerebellar ataxia type 17.

151. The method of claim 149, wherein the polyglutamine disease is Huntington’s disease.

152. The method of any one of claims 142-148, wherein the repeat expansion disease is myotonic dystrophy type 1.

153. The method of any one of claims 142-148, wherein the repeat expansion disease is spinocerebellar ataxia type 8.

154. The method of any one of claims 142-148, wherein the repeat expansion disease is Huntington's disease-like 2 (HDL2).

155. The method of any one of claims 142-148, wherein the repeat expansion disease is Fuchs comeal dystrophy.

Images