Peptide trans-membrane delivery systems and uses thereof

Abstract

The present invention is directed to peptide conjugates of the invention, pharmaceutical composition comprising same and to methods for use thereof, such as for the treatment and / or prevention of a disease in a subject.

Description

PEPTIDE TRANS-MEMBRANE DELIVERY SYSTEMS AND USES THEREOFREFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0001] The contents of the electronic sequence listing (APSN-P-013-PCT.xml; size: 6,714 bytes; and date of creation: March 27, 2024) is herein incorporated by reference in its entirety.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority of U.S . Provisional Patent Application No. 63 / 454,786, titled "PEPTIDE TRANS-MEMBRANE DELIVERY SYSTEMS AND USES THEREOF", filed March 27, 2023 and of U.S. Provisional Patent Application No. 63 / 566,959, titled "PEPTIDE TRANS-MEMBRANE DELIVERY SYSTEMS AND USES THEREOF", filed March 19, 2024. The contents of which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION

[0003] There are numerous peptides showing significant biological activity and which can be potentially utilized as a therapeutically active ingredient in pharmaceutical preparations. Current pharmaceutical research is focused on peptides facilitating targeting of intracellular protein-protein interaction, which is almost impossible using small molecule - based drugs.

[0004] Although peptides are more stable in biological medium as compared to other biopolymers such as oligonucleotides, however most of them lack the ability to penetrate the cell membrane.

[0005] Currently, the main approach to improve cell penetration is by conjugating the therapeutic peptide sequence to a cell penetrating peptide (CPP) that lacks any therapeutic activity and acts as a carrier by helping the therapeutic peptide to surpass the cell membrane. Many CPPs show their powerful penetrating activity only above high micromolar concentrations (>10 pM). For the delivery of mid- or large-size drugs, these concentrations are hardly acceptable in clinics. Therefore, the penetration efficiency needs to be enhanced to achieve lower and meaningful clinical concentrations.

[0006] To this end, the major obstacle in the implementation of peptides in the treatment of a disease is their negligible cellular penetration. Accordingly, there is a long-felt but unsolved need for safe and efficient means for intracellular delivery of peptides.SUMMARY OF THE INVENTION

[0007] In one aspect of the invention, there is provided a conjugate comprising a polymer covalently bound to a moiety represented by Formula 1 including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof:, wherein: a and b each independently represents an integer being between 1 and 10; L represents a linker comprising at least one -N(R5)- group, and wherein the linker is between 1 and 30 single C-C bonds long; R represents one or more substituents, each independently is selected from halo, -NO2, -CN, -OH, -CONH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, - CONH-NH2, oxo, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=0)NR’, - NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, - NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl- C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl -SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R’, -OCOR, -OCOR’, - OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; R5 is H or a straight or branched optionally substituted Cl - C5 alkyl, optionally comprising one or more heteroatoms; a wavy bond represents an attachment point to the polymer; and wherein the polymer comprises a peptide, or a polymer comprising a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, maleimide, an active ester, an alpha, beta-unsaturated keto acid derivative or any combination thereof.

[0008] In one embodiment, the moiety is represented by Formula 2:, wherein: c is an integer independently selected from 0 to 10; LI is a bond, or a linker selected from - N-C(=O)-, -C(=O)N-, -S-S-, -S-C(=O), Y-(Co-io)alkyl-X-(Co-io)alkyl-Y, and a click reaction product, or any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, - CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, - OC(=O)O-, -OC(=S)O-, and -OC(=S)N-; the oligomer comprises between 2 and 15 repeating units; and W represents (i) an amide, (ii) a click reaction product, or both.

[0009] In one embodiment, the repeating unit is selected from: alkylene oxide, a natural or an unnatural amino acid derivative, alpha-hydroxy carboxylic acid residue, and an amino group.

[0010] In one embodiment, LI is -N-C(=O), -C(=O)N, or Y-(Co-io)alkyl-X-(Co-io)alkyl-Y.

[0011] In one embodiment, the moiety is represented by Formula 3:

[0012] In one embodiment, the click reaction product comprises succinimide-thioether, azide alkyne cycloaddition product, direct and / or inverse electron demand Diels Alderreaction product, dibenzyl cyclooctyne 1,3 -nitrone cycloaddition product, or any combination thereof.

[0013] In one embodiment, the polymer is a polynucleotide substituted by one or more of: a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, maleimide, an active ester, an alpha, beta-unsaturated keto acid derivative or any combination thereof.

[0014] In one embodiment, the moiety is bound to (i) the N-terminus of the peptide, or to the C-terminus of the peptide, (ii) to the C-terminal amino acid of the peptide, (iii) at least one of: an amino group and a thio group of an amino acid residue of the peptide, or any combination of (i)-(iii).

[0015] In one embodiment, the moiety is represented by Formula 4:wherein n is integer independently selected from 1 to 10; and wherein each Y1 and Y2 is absent or is independently selected from -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, - NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O- , and -OC(=S)N-.

[0016] In one embodiment, Y1 is -N-C(=O)-, and Y2 is -N-C(=O)- or -C(O=)O-.

[0017] In one embodiment, R5 is methyl.

[0018] In one embodiment, R is a halogen.

[0019] In one embodiment, the conjugate is selected from:

[0020] In one embodiment, the conjugate is derived from any of the compounds listed in Table A or B (i.e. the conjugate is obtained by conjugation of the precursor of Table A or B with the polymer).

[0021] In another aspect, there is provided a compound, including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof; wherein the compound is represented by Formula 5:a and b each independently represents an integer being between 1 and 10; M represents a linker comprising at least one -N(R5)- group; the linker is between 1 and 30 single C-C bonds long; Z is a moiety having a reactivity to a functional group selected from a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, succinimide, alpha, beta unsaturated carbonyl, alpha, beta unsaturated keto acid derivative, and active ester, or any combination thereof; R represents one or more substituents, each independently is selected from halo, -NO2, -CN, -OH, -CONH2, -CONR’2, -CNNR’2, -CSNR’2, -CONH- OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR’, - NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, - NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl- C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl -SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R’, -OCOR, -OCOR’, - OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; R5 is H or a straight or branched optionally substituted Cl - C5 alkyl, optionally comprising one or more heteroatoms.

[0022] In one embodiment, the compound is represented by Formula 6:, wherein: c is an integer selected from 1 to 10;LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-S-, -S-C(=O), Y- (Co-io)alkyl-X-(Co-io)alkyl-Y, including any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, - NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, - OC(=S)O-, -OC(=S)N-; the oligomer comprises between 2 and 15 repeating units.

[0023] In one embodiment, LI is -N-C(=O), -C(=O)N, or Y-(C0-10)alkyl-X-(C0-10)alkyl- Y.

[0024] In one embodiment, the compound is represented by Formula 7:

[0025] In one embodiment, the compound is represented by Formula 8:wherein n is integer independently selected from 1 to 10; and wherein each Y1 and Y2 are independently selected from -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -0C(=0)0-, -OC(=S)O-, and -OC(=S)N-.

[0026] In one embodiment, Y1 is -N-C(=O)-, and Y2 is -N-C(=O)- or -C(O=)O-.

[0027] In one embodiment, Z is selected from an active ester, an alpha-beta unsaturated keto compound, and maleimide.

[0028] In one embodiment, R is halo, and R5 is methyl.

[0029] In one embodiment, the compound is selected from:

[0030] In one embodiment, Z has reactivity to a polymer comprising the functional group; and wherein the compound is a precursor of the conjugate of the invention.

[0031] In another aspect, there is provided a pharmaceutical composition, comprising the conjugate of the invention and a pharmaceutically acceptable carrier.

[0032] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the conjugate.

[0033] In one embodiment, the pharmaceutical composition is for use in the treatment or prevention of a disease in a subject.

[0034] In one embodiment, the disease is cancer.

[0035] In another aspect, there is provided a kit comprising the compound of the invention, and a polymer selected from (i) a peptide; and (i) a polymer comprising a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, or any combination thereof.

[0036] In one embodiment, a molar ratio between the polymer and the compound within the kit is about 1:1.

[0037] In one embodiment, the kit further comprises instructions for reacting the polymer and the compound to obtain the conjugate of the invention.

[0038] In one embodiment, the kit further comprises a liquid carrier.

[0039] In another aspect, there is provided a method for treating a disease or condition within a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of the invention to the subject, thereby treating the disease.

[0040] In one embodiment, the disease is a cell proliferation related disease.

[0041] In another aspect, there is provided a method for internalizing a peptide into a cell of a subject, comprising contacting the cell with the pharmaceutical composition of the invention, thereby internalizing the peptide into the cell.

[0042] In one embodiment, the cell is a cancer cell.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0044] Fig. 1. is a graph bar representing Bl 6- melanoma cell viability (normalized to the relevant control) after exposure to exemplary conjugate of the invention comprising JNK- peptide as an exemplary therapeutic sequence. Amino acid sequences of the tested conjugates and controls are presented in Table 1.

[0045] Fig. 2. is a graph bar representing Hela cell viability after exposure to exemplary conjugate of the invention. #1, 2 and 3 refer to CPP, Control 2 and Control 1, respectively. Amino acid sequences of the tested conjugates and controls are presented in Table 1.

[0046] Fig. 3. is a graph bar representing Bl 6- melanoma cell viability (normalized to the relevant control) after exposure to exemplary conjugate of the invention comprising JNK- peptide as an exemplary therapeutic sequence. Amino acid sequences of the tested conjugates and controls are presented in Table 3.DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0047] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0048] In one aspect of the invention, there is provided a conjugate comprising a polymer covalently bound to a moiety represented by Formula A’:wherein a and b each independently represent an integer being between 1 and 10; A represents a sterol; RT is an optionally substituted alkyl or an optionally substituted heteroalkyl; L represents a linker comprising at least one - N(R5)- group, and wherein the linker is between 1 and 30 single C-C bonds long; each Rindependently represents a substituent or H; wherein a wavy bond represents an attachment point to the polymer; and wherein the polymer is or comprises a poly aminoacid (e.g. cyclic or linear peptide, protein, or any copolymer thereof), polyethyleneimine (PEI), or a polymer comprising an amino acid and further comprising a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, maleimide, an active ester, an alpha, beta-unsaturated keto acid derivative or any combination thereof; and wherein each R is hydrogen or represents one or more substituents, each independently selected from halo, -NO2, -CN, -OR’, -OH, - C0NH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, - C0NH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, - NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, - NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -COR’, -C02R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6alkyl), Ci-C6mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, - OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof. In some embodiments, the sterol is selected from a phytosterol, a zoosterol, an ergosterol and a steroid. In some embodiments, the polymer is bound to a plurality of moieties (e.g. 2, 3, 4, or 5 moieties).

[0049] In another aspect of the invention, there is provided a conjugate comprising a polymer covalently bound to a moiety represented by Formula B’: / vv'L BbTwherein b represents an integer being between 1 and 10; A represents a sterol; B represents at least one of an optionally substituted C3-C10 cycloalkyl, an optionally substituted C3-C10 heterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl; RT is an optionally substituted alkyl or an optionally substituted heteroalkyl; L represents a linker being between 1 and 30 single C-C bonds long; and a wavy bond represents an attachment point to the polymer. In some embodiments, RTis a heteroalkyl comprising at least two heteroatoms (e.g. O and / or S), and further substituted by a C3-C5 linear or branched alkyl (e.g. -C(CH3)3), or by a C3-C5 linear or branched haloalkyl, or by a C3-C5 linear or branched fluoroalkyl (e.g. -C(CF3)3).

[0050] In some embodiments, the moiety of the invention is represented by Formula A”:d above; wherein b represents an integer being between 1 and 10; A represents a sterol; B represents at least one of an optionally substituted C3-C10 cycloalkyl, an optionally substituted C3- C10 heterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl; RT is an optionally substituted alkyl or an optionally substituted heteroalkyl; L represents a linker being between 1 and 30 single C-C bonds long; and a wavy bond represents an attachment point to the polymer.

[0051] In some embodiments, the moiety of the invention is represented by Formula A’ 1 :wherein each X independently represents H or one or more alkyls (e.g. one or more methyl groups). In some embodiments, the sterol is cholesterol.

[0052] In some embodiments, the moiety of the invention is represented by Formula 1A:

[0053] In some embodiments, the moiety of the invention is represented by Formula 1, or by any of Formulae disclosed herein, including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof. In some embodiments, the polymer of the invention includes any stereoisomer, any salt, or any hydrate thereof.

[0054] In some embodiments, R is H or represents one or more substituents each independently selected from, halo, -NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, - NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, - SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, - OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6 alkyl), Ci-Ce mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, - OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combinationthereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof. In some embodiments, the conjugate comprises a plurality of moieties of the invention (such as 2, 3, or 4 moieties) covalently bound to a single molecule of the polymer.

[0055] The term “polymer comprising an amino acid and further comprising a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, maleimide, an active ester, and / or an alpha, beta-unsaturated keto acid derivative”, as disclosed herein refers to the polymer in its unconjugated form (i.e., in the original form before being conjugated to the moiety of the invention). A skilled artisan will appreciate, that in the conjugated form (i.e., within the conjugate of the invention) the thio group, amino group, alpha, beta-unsaturated keto acid derivative, etc. of the polymer generate a covalent bond with the moiety. Accordingly, the abovementioned groups of the polymer in the conjugated form undergo chemical modification, for example: amino group reacts with an active ester to form an amide bond, the alpha, beta-unsaturated keto acid derivative undergoes a Michael addition, so as to form a compound of Formula A or of Formula B, as disclosed hereinbelow.

[0056] In some embodiments, the polymer in the unconjugated form comprises a functional group selected from a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, maleimide, an active ester, and / or an alpha, beta-unsaturated keto acid derivative, or any combination thereof. In some embodiments, the polymer in the conjugated form is bound to L via the functional group (i.e. a chemically modified functional group, as disclosed above). In some embodiments, the wavy bond of the conjugate of the invention represents a linkage between the functional group (i.e., a chemically modified functional group) of the polymer and L of the moiety.

[0057] In some embodiments, the alpha, beta-unsaturated keto acid derivative is represented by Formula A:B, wherein X is NH, S or 0; wherein R” represents a hydrogen, or is selected from the group comprising optionally substituted Ci- Cio alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; and wherein the dashed bond represents attachment point to the polymer (e.g., peptide) and the wavy bond represents attachment point to the linker L of the moiety of the invention (or vice versa), or any combination thereof. In some embodiments, R” is a substitute aryl, aryl. In some embodiments, R” is benzyl.

[0058] In some embodiments, the conjugate of the invention comprises the polymer bound to at least 1 moiety, or to a plurality of moieties selected from 2 moieties, between 1 and 4, between 1 and 3 moieties of the invention (as defined by Formula 1 or any subsequent Formulae disclosed herein), including any range in between. In some embodiments, the polymer is a peptide, wherein the plurality of moieties are bound to the peptide at the same location or at different locations within the peptide sequence (e.g. N-terminus of the peptide, C-terminus of the peptide, and / or via any of the side chain residues within the peptide sequence).

[0059] In some embodiments, the polymer is covalently bound to the linker via a bond selected from amide bond, ester bond, S-S bond, and a click reaction product, including any combination thereof. In some embodiments, the linker comprises an optionally substituted C1-C10 alkyl, a heteroatom (e.g., O, N, NH, or S), -C(O)NH-, -C(O)O-, -C(O)-, -C(O)S-, - C(NH)NH-,- C(NH)O-,-C(NH)S-, a C1-C10 aminoalkyl, a C1-C10 alkoxy, a C1-C10 mercaptoalkyl, -S-S-, -S-C(=O), Y-(C0-10)alkyl-X-(C0-10)alkyl-Y, or a click reactionproduct including any combination thereof; wherein each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’- , -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)N-. In some embodiments, the oligomer comprises between 2 and 15 repeating units. In some embodiments, the repeating unit is selected form alkylene oxide, a natural or an unnatural amino acid residue (i.e. an amino acid lacking a hydrogen atom of the amino group and the hydroxyl moiety of the carboxyl group; exemplary amino acid residues are glycine, alanine, and / or beta alanine residue), an alpha-hydroxy carboxylic acid residue (i.e. alpha-hydroxy carboxylic acid lacking a hydrogen atom of the alpha-hydroxy group and the hydroxyl moiety of the carboxyl group; such as lactic acid residue, and / or glycolic acid residue), including any copolymer and any combination thereof. In some embodiments, the linker is devoid of S-S bond.

[0060] In some embodiments, the repeating unit of the oligomer comprises an amine. In some embodiments, the repeating unit of the oligomer comprises an amine, selected from:ethylene amine, or to a polyethyleneimine chain, including any copolymer and any combination thereof.

[0061] In some embodiments, the linker is between 1 and 30, between 1 and 20, between 1 and 10, between 1 and 5, between 5 and 10, between 5 and 15, between 5 and 25 single C- C bonds long, including any range in between.

[0062] In some embodiments, the linker is characterized by an average molecular weight between 30 and 10,000Da, between 30 and 5,000Da, between 30 and l,000Da, between 100 and l,500Da, between 300 and l,000Da, between 300 and 5,000Da, between 300 and 2000, between 300 and 3,000Da, between 300 and 10,000Da, including any range inbetween. In some embodiments, the linker is characterized by an average molecular weight between 300 and 3,000Da, and is between 2 and 30, between 2 and 10, between 2 and 20, C-C bonds long, including any range between.

[0063] In some embodiments, the oligomer comprises between 2 and 15, between 2 and 5, between 2 and 10, between 2 and 7, between 5 and 15, between 3 and 8 repeating units, including any range in between, wherein the repeating unit is as described hereinabove. In some embodiments, the oligomer comprises or consists essentially of repeating units having the same chemical composition. In some embodiments, the oligomer comprises or consists essentially of chemically distinct repeating units (e.g., in a form of a copolymer, a random copolymer, a block-copolymer, etc.).

[0064] In some embodiments, the oligomer is characterized by an average molecular weight between 30 and lOOODa, between 30 and lOODa, between 30 and 200Da, between 30 and 300Da, between 30 and 400Da, between 30 and 500Da, between 30 and 600Da, between 30 and 700Da, between 30 and 800Da, between 30 and 900Da, between 100 and 300Da, between 50 and 350Da between 100 and 500Da between 150 and 500Da between 100 and 900Da including any range in between.

[0065] In some embodiments, the oligomer is or comprises a plurality of ethylene oxide repeating units, i.e., polyethylene glycol (PEG).

[0066] In some embodiments, the term “click reaction” refers to highly efficient and highly selective reaction with a reaction yield of almost 100%, along with negligible by products formation. The click reaction forms a covalent bond (conjugation) between two reactive groups attached to the same molecule or to different molecules. The reactive groups have a superior reactivity to each other and have only a negligible reactivity to any other functional group, thereby resulting in a highly specific / selective reaction. In some embodiments, the click reaction enables a specific conjugation of two different molecules (such as two polymers or a polymer and a small molecule).

[0067] In some embodiments, click reactions are well-known in the art and comprise inter alia Michael addition of maleimide and thiol (resulting in the formation of a succinimidethioether); Michael addition of alpha, beta unsaturated keto acid derivative and a thiol; azide alkyne cycloaddition; Diels-Alder reaction (e.g., direct and / or inverse electron demand Diels Alder); dibenzyl cyclooctyne 1,3 -nitrone (or azide) cycloaddition; alkene tetrazolephoto-click reaction, etc. In some embodiments, the alpha beta-unsaturated keto acid derivative is represented by the Formula A and B, as disclosed hereinabove.

[0068] In some embodiments, the click reaction product comprises succinimide-thioether, azide alkyne cycloaddition product, direct and / or inverse electron demand Diels Alder reaction product, dibenzyl cyclooctyne 1,3 -nitrone cycloaddition product, or a compound of Formula A and / or of Formula B .

[0069] In some embodiments, succinimide-thioether is:, wherein (i) the wavy bond represents attachment point to the linker L of the moiety of the invention and the dashed bond represents attachment point to the polymer (e.g., peptide); or (ii) the wavy bond represents attachment point to the polymer (e.g., peptide) and the dashed bond represents attachment point to the linker L of the moiety of the invention.

[0070] In some embodiments, the click reaction product comprises a moiety formed via a click reaction, wherein the click reaction is as described hereinabove. In some embodiments, the click reaction product comprises a product formed by any of: Michael addition of maleimide and thiol (resulting in the formation of a succinimide-thioether); azide alkyne cycloaddition; Diels-Alder reaction (e.g., direct and / or inverse electron demand Diels Alder); dibenzyl cyclooctyne 1,3-nitrone (or azide) cycloaddition; alkene tetrazole photoclick reaction, or any combination thereof.

[0071] In some embodiments, the moiety is represented by Formula 2:wherein W,R, R5, a and b are as disclosed above; wherein m is an integer independently selected from 1 to 5; each Xi is independently O, S, NR5, CRR or CH2; Rn comprises an optionally substituted liner or branched alkyl, or a linear or branched haloalkyl; c is an integer independently selected from 0 to 10;LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-S-, -S-C(=O), Y-(Co- io)alkyl-X-(Co-io)alkyl-Y, a cycloalkyl, a heterocyclyl and a click reaction product, or any combination thereof.

[0072] In some embodiments, the moiety is represented by Formula 2’ :, whereinR, R5, a, b, m are as disclosed above; c is an integer independently selected from 0 to 10; LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-S-, -S-C(=O), Y-(Co- io)alkyl-X-(Co-io)alkyl-Y, including any combination thereof; W is absent, or represents (i) an amide, (ii) a click reaction product, or both; a wavy bond represents an attachment point to the polymer; and the polymer is selected from a peptide and a polymer comprising a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, or any combination thereof.

[0073] In some embodiments, R represents at least 2 substituents each independently selected from F, Cl, Br and I. In some embodiments, R represents 2, 3 or 4 substituents,each independently selected from F, Cl, Br and I. In some embodiments, R represents 2, 3 or 4 fluoro substituents. In some embodiments, at least one R is F.

[0074] In some embodiments, R5 is H or a straight or branched Cl - C5 alkyl. In some embodiments, C1-C5 alkyl comprises of 1, 2, 3, 4 or 5 carbon atoms. In some embodiments, R5 is methyl.

[0075] In some embodiments, the moiety is represented by Formula 2 A:wherein R, R5, LI, W, a, b, and c, are as disclosed herein above; d and e each independently is an integer independently selected from 1 to 10. In some embodiments, W is or comprises an amide, a succinimide-thioether, azide alkyne cycloaddition product, direct and / or inverse electron demand Diels Alder reaction product, dibenzyl cyclooctyne 1,3 -nitrone cycloaddition product, or a compound of Formula A and / or of Formula B.

[0076] In some embodiments, the moiety is represented by Formula 2B:

[0077] In some embodiments, the moiety is represented by Formula 2C:wherein R’ is as disclosed herein above. In some embodiments, R’ is benzyl.

[0078] In some embodiments, the moiety is represented by Formula 2D:

[0079] In some embodiments, LI is -N-C(=O), -C(=O)N or Y-(Co-io)alkyl-X-(Co-io)alkyl- Y.R'

[0080] In some embodiments, X, wherein R’ is as disclosed above; wherein n is an integer independently selected from 1 to 15; and wherein the wavy bondrepresents attachment point to polymer (e.g., peptide) or the linker of the moiety of the invention. In some embodiments, R’ is hydrogen.

[0081] In some embodiments, n is between 1 and 15, between 1 and 3, between 1 and 5, between 1 and 7, between 1 and 10, between 2 and 15, including any range in between.

[0082] In some embodiments, the moiety is represented by Formula 3:between 1 and 10, optionally wherein at least one XI is -O-; or by Formula 3’ :

[0083] In some embodiments, the moiety is represented by Formula 3A:

[0084] In some embodiments, the moiety is represented by Formula 4:wherein, R, R5, W, a, b, c, d, e and n are as disclosed above; and wherein each Y 1 and Y2 are independently selected from -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, -OC(=S)N- , cycloalkyl, a heterocyclyl, and wherein R’ is as disclosed above. In some embodiments, Y1 is -C(=O)NH-. In some embodiments, Y1 and Y2 are -C(=O)NH-. In some embodiments, Y2 is -C(=O)O. In some embodiments, Y2 is absent. In some embodiments, the moiety is represented by Formula 4 or 4’, wherein: b is 1 and a is 3.

[0086] In some embodiments, the moiety is represented by Formula 9:, wherein each X2 is independentlyN, or CR; each R is independently hydrogen or represents one or more substituents, each independently selected from halo, -NO2, -CN, -OR’, -OH, -C0NH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -C0NH-NH2, -NHCOR’, - NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, - SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -COR’, -C02R’, -OCOR’, -OCOR’, -OC(=O)OR’, - OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6 alkyl), Ci-Ce mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, - OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; and wherein L and RT are as described above.

[0087] In some embodiments, the moiety is represented by Formula 10:wherein XI, c, LI, m, R, b, L and RTI are as described above. In some embodiments, the moiety is represented by Formula 10 wherein LI is a bond; an wherein at least one XI is CRR, and each R is independently hydrogen or represents one or more substituents, each independently selected from -NO2, -CN, -OR’, -OH, -CONH2, -CONR’2, -CNNR’2, - CSNR’2, -CONH-OH, -CONH-NH2, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, - NC(=S)NR’, -SO2R’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH2, -NR’R’, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, or a combination thereof. In some embodiments, the moiety is represented by Formula 10 wherein LI is a bond; an wherein XI is CRR (e.g. methylene).

[0088] In some embodiments, the moiety is represented by Formula 10A:, wherein c, m, b, XI, LI, R andRTI are as described above; and wherein X’ represented O-Et.

[0089] In some embodiments, the moiety is represented by any of Formulae above, wherein

[0090] In some embodiments, the moiety is represented by Formula 10B:, wherein c, m, b, XI, X’, LI, R are as described above; and wherein RTI is -C(CF3)3.

[0091] In some embodiments, the moiety of the invention is derived (i.e. chemically modified upon conjugation thereof with the polymer) from any one of the precursors of Table A.

[0092] In some embodiments, the polymer disclosed herein comprises an amino group bound thereto. In some embodiments, the polymer comprises a side chain bound to the backbone of the polymer, wherein the side chain comprises any one of: a thio group, an amino group, 1,3-nitro, azide, a diene, tetrazine, or any combination thereof. In some embodiments, the amino group is a side chain bound to the backbone of the polymer. In some embodiments, the amino group is a primary amine. The term “primary amine” describes an amine that its amino group is directly bound to only one carbon. In some embodiments, the conjugate of the invention is a reaction product of the amino group or thio group of the polymer and Z of the precursor, as disclosed hereinbelow.

[0093] In some embodiments, the polymer is or comprises polyethylene imine. In some embodiments, the polymer comprises at least one amino acid.

[0094] In some embodiments, the polymer is characterized by an average molecular weight between 1000 and 5000Da, between 1500 and 4500Da, between 2000 and 4000Da, between 2500 and 3500Da, between 1000 and 2000Da, between 1000 and 3000Da, between 1000 and 4000Da, between 3000 and 5000Da, including any range in between.

[0095] In some embodiments, the polymer is a peptide (also used herein as “polyamino acid”). In some embodiments, the polymer is a random polyaminoacid. In some embodiments, the peptide comprises or consists essentially of a therapeutically affective amino acid sequence and further comprises a cell-penetrating peptide bound to the therapeutically affective amino acid sequence.

[0096] As used herein, the terms “polyamino acid”, “peptide”, "polypeptide" and "protein" are used interchangeably and refer to a polymer of amino acid residues. In some embodiments, the polymer has an amino acid sequence. In some embodiments, the entire polymer species of the composition / conjugate / precursor of the invention have the same amino acid sequence.

[0097] The terms "peptide", "polypeptide" and "protein" as used herein encompass native peptides, peptide derivatives such as beta peptides, peptidomimetics (typically including non-peptide bonds or other synthetic modifications,) and the peptide analogs peptoids and semi-peptoids or any combination thereof. In another embodiment, the terms “peptide”, "polypeptide" and "protein" apply to amino acid polymers in which at least one amino acid residue is an artificial chemical analog of a corresponding naturally occurring amino acid.

[0098] The term "derivative" or "chemical derivative" includes any chemical derivative of the polypeptide having one or more residues chemically derivatized by reaction on the side chain or on any functional group within the peptide. Such derivatized molecules include, for example, peptides bearing one or more protecting groups (e.g., side chain protecting group(s) and / or N-terminus protecting groups), and / or peptides in which free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, acetyl groups or formyl groups. Free carboxyl groups may be derivatized to form amides thereof, salts, methyl and ethyl esters or other types of esters or hydrazides. Free hydroxyl groups may be derivatized to form O- acyl or O-alkyl derivatives. Free thiol groups may be derivatized to form S-S bonds, thioester or S-alkyl derivatives. The imidazole nitrogen of histidine may be derivatized to form N-im-benzylhistidine. Also included as chemical derivatives are those peptides, whichcontain one or more naturally occurring amino acid derivatives of the twenty standard amino acid residues. For example: 4-hydroxyproline may be substituted for proline; 5- hydroxylysine may be substituted for lysine; 3 -methylhistidine may be substituted for histidine; homoserine may be substituted or serine; and Dab, Daa, and / or ornithine (O) may be substituted for lysine.

[0099] In addition, a peptide derivative can differ from the natural sequence of the peptide of the invention by chemical modifications including, but are not limited to, terminal-NH2 acylation, acetylation, or thioglycolic acid amidation, and by amidation of the terminal and / or side-chain carboxy group, e.g., with ammonia, methylamine, and the like. Peptides can be either linear, cyclic, or branched and the like, having any conformation, which can be achieved using methods known in the art.

[0100] The term "amino acid" as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are naturally occurring amino acids, protected amino acids (e.g., comprising one or more protecting groups at the carboxyl, at the amine, and / or at the side chain of the amino acid), unusual, non-naturally occurring amino acids (such as D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides. 5: 342-429. Modified, unusual or non-naturally occurring amino acids include, but are not limited to, D- amino acids, hydroxy lysine, 4-hydroxyproline, N-Cbz-protected aminovaleric acid (Nva), ornithine (O), aminooctanoic acid (Aoc), 2,4-diaminobutyric acid (Abu), homoarginine, norleucine (Nle), N-methylaminobutyric acid (MeB), 2-naphthylalanine (2Np), aminoheptanoic acid (Ahp), phenylglycine, P-phenylproline, tert-leucine, 4- aminocyclohexylalanine (Cha), N-methyl-norleucine, 3,4-dehydroproline, N,N- dimethylaminoglycine, N-methylaminoglycine, 4-aminopipetdine-4-carboxylic acid, 6- aminocaproic acid, trans-4- (aminomethyl) - cyclohexanecarboxylic acid, 2-, 3-, and 4- (aminomethyl) - benzoic acid, 1 -aminocyclopentanecarboxylic acid, 1- aminocyclopropanecarboxylic acid, cyano-propionic acid, 2-benzyl-5- aminopentanoic acid, Norvaline (Nva), 4-O-methyl-threonine (TMe), 5-O-methyl-homoserine (hSM), tert- butyl-alanine (tBu), cyclopentyl-alanine (Cpa), 2-amino-isobutyric acid (Aib), N-methyl- glycine (MeG), N-methyl-alanine (MeA), N-methyl-phenylalanine (MeF), 2-thienyl-alanine (2Th), 3 -thienyl- alanine (3Th), O-methyl-tyrosine (YMe), 3-Benzothienyl-alanine (Bzt) and D-alanine (DAI).

[0101] In some embodiments, the peptide sequence is or comprises D-amino acid sequence. In some embodiments, at least 70%, at least 80%, at least 90%, at least95% of the amino acids within the peptide sequence are in D-configuration. In some embodiments, the amino acids within the peptide sequence are in D-configuration. In some embodiments, the peptide is bound to one or more moieties of the invention. In some embodiments, the moiety of the invention is covalently bound via: (i) the N terminus of the peptide; (ii) the C terminus of the peptide and / or (iii) to a side chain within the peptide sequence (e.g. amino or thio group of the amino acid residue). In some embodiments, the N terminus of the peptide is bound to W. In some embodiments, the C terminus of the peptide is bound to W. In some embodiments, a side chain of an amino acid within the peptide sequence is bound to W.

[0102] In some embodiments, the peptide sequence is a therapeutic sequence. As used herein, the term "therapeutic sequence" refers to a polyamino acid configured for inducing a therapeutic effect within a subject (e.g., treating, preventing, reducing symptoms of a disease, etc.). Further, the term "therapeutic sequence" encompasses any polyamino acid sequence capable of modifying the activity, functionality, survival, fitness, appearance, structure, development, behavior, or any combination thereof, of a cell. In some embodiments, the therapeutic sequence is capable of binding an intracellular target, so as to control (upregulate, or downregulate) the activity of the intracellular target. In some embodiments, the intracellular target is selected from an intracellular protein, enzyme, receptor, or any combination thereof. In some embodiments, the therapeutic sequence in an endogenous or exogenous sequence. As used herein, the term "endogenous" refers to the fact that a compound is naturally produced in or by the contacted cell.

[0103] In some embodiments, the therapeutic sequence is an apoptosis inducer. The term "apoptosis inducer" encompasses any polyamino acid sequence capable of inducing or promoting programmed cell death.

[0104] In some embodiments, the conjugate further comprises a cell penetrating peptide (CPP) covalently bound to (i) the moiety of the invention via the linker disclosed herein, or (ii) is covalently bound to the peptide (i.e. not necessarily bound to the moiety of the invention). In some embodiments, the CPP is covalently bound to the moiety via a reactivegroup of the linker, such as OH, carboxy, amino, thio, sulfo, etc. In some embodiments, the moiety is represented by Formula 2, wherein Xi is CRR, and wherein one of R is a reactive group bound to or having reactivity to the CPP (e.g. to an amino, carboxy, or thio group of the CPP).

[0105] In some embodiments, the CPP is covalently bound to the polymer (peptide) and / or to the linker of the invention. In some embodiments, CPP is bound to the linker of the invention and to the peptide, as illustrated below:Peptideor CPP - Peptidewherein the wavybond represent attachment to the moiety of the invention, wherein W is as described herein, and wherein “peptide” is the peptide sequence (also referred to herein as “cargo”). In some embodiments, the CPP is bound to the N terminus of the peptide. In some embodiments, the CPP is bound to the C terminus of the peptide. In some embodiments, the CPP is bound to a side chain of an amino acid within the peptide sequence, or to the backbone of the peptide.

[0106] In some embodiments, the conjugate of the invention comprises a cargo covalently bound to a carrier, wherein the carrier is or comprise the moiety of the invention. In some embodiments, the cargo comprises a peptide or the polymer as disclosed herein to be delivered into a cell of a subject. In some embodiments, the cargo is or comprises the peptide or the polymer as disclosed herein, and wherein the cargo is a therapeutic cargo. The term “therapeutic cargo” refers to any peptide having a therapeutically affective amino acid sequence configured for inducing a therapeutic effect within a subject (e.g., treating, preventing, reducing symptoms of a disease, etc.). Further, the term "therapeutic cargo" encompasses any polyamino acid sequence, or a sequence of a polymer (e.g. oligonucleotide sequence) capable of modifying the activity, functionality, survival, fitness, appearance, structure, development, behavior, or any combination thereof, of a cell. In some embodiments, the therapeutic cargo is capable of binding an intracellular target, so as to control (upregulate, or downregulate) the activity of the intracellular target. In some embodiments, the conjugate further comprises CPP covalently bound to (i) the moiety of the invention via the linker disclosed herein, or (ii) is covalently bound to the polymer of the invention or to the peptide (i.e. not necessarily bound to the moiety of the invention). In some embodiments, the carrier comprises the moiety of the invention and CPP. As demonstrated in the Examples section below, the inventors surprisingly observed that a conjugate comprising a combination of a CPP and the moiety of the invention as the carrierhas superior cell internalization over a similar conjugate comprising the moiety of the invention as the sole carrier (without CPP).

[0107] The term “cell penetrating peptides (CPP)” refers to a peptide covalently bound to the cargo molecule and is capable of enhancing or inducing penetration of the cargo molecule (i.e. a peptide) into the cell. The CPP may be of between 4 and 30, between 4 and 50, between 8 and 20, between 8 and 25, between 8 and 30 amino acid residues long, including any range between. In some embodiments, the CPP is a linear or a cyclic peptide. CPPs are usually either multiply positively charged under neutral pH, and / or comprise a specific sequence configured to penetrate cell membrane (usually by endocytosis) and to shuffle the cargo into the cell.

[0108] The term “CPP” encompasses positively charged CPPs, negatively charged CPPs and amphipathic CPPs.

[0109] Positively charged CPPs comprise multiple (at least 3) [positively charged amino acid residues (i.e. Lys, Arg, and / or His). Positively charged CPPs are configured inter alia to electrostatically bind a negatively charged cell membrane under physiological conditions (e.g. pH value of between about 65. -7.5). Non-limiting examples of positively charged CPPs include multiple lysine and / or arginine-based peptides such as R4-9, K4-9, Xentry and TAT.

[0110] Amphipathic CPPs usually comprise both positively charged amino acid residues and hydrophobic amino acid residues (e.g. Trp, Phe, He, Tyr, Phe and Met). Positively charged and hydrophobic amino acid residues may be separated in two distinct blocks, or may be intermixed within the CPP sequence.

[0111] Non-limiting examples of amphipathic CPPs are Penetratin, Transportan, pVEC, MAP, Pep-1, MPG and VT5.

[0112] Non-limiting examples of negatively charged CPPs (i.e. negatively charged at neutral pH of between about 6.5-7.5 or between 6 and 8) include (i) sweet arrow peptides - S AP(E) having a high proline content and configured to adopt a helical secondary structure, and (ii) Azurin-derived p28.

[0113] In some embodiments, the moiety of the invention (as defined by Formula 1 or any subsequent Formulae disclosed herein) is a carrier configured for enhancing or inducing cellular internalization of the polymer, wherein the polymer is as described herein. In some embodiments, the moiety of the invention is a peptide carrier. In some embodiments, the carrier comprises the moiety of the invention and a CPP. In some embodiments, the CPP iscovalently bound to the moiety (e.g. via L). In some embodiments, the CPP and the moiety are bound to the polymer. In some embodiments, the CPP and the moiety are independently bound to the polymer at different locations. In some embodiments, the carrier comprises CPP and the moiety covalently bound to each other (e.g. via L), and wherein the carrier is covalently bound to the polymer via the CPP (e.g. at N-terminus of the CPP, at C-terminus of the CPP, or via a side chain of an amino acid residue located within the sequence of the CPP).

[0114] In some embodiments, the polymer of the invention is a peptide. In some embodiments, the polymer of the invention is or comprises a therapeutic peptide sequence. In some embodiments, the peptide is or comprises an amino acid sequence selected from the sequences disclosed in Table 1. SEQ ID NO: 1 refers to an exemplary non-limiting therapeutic peptide sequence (JNK) used in Example 7. SEQ ID NO: 2 refers to JNK bound to an exemplary CPP (Tat, SEQ ID NO: 4).Table 1: exemplary peptide sequences and control sequences (without the moiety of the invention)* is an attachment point to “W” (amide bond)** is attachment point to “W” via cysteine side chain& is attachment point to “W” via lysine side chain The CPP sequence is highlighted in boldPrecursor

[0115] In another aspect, there is provided a compound, including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof; wherein the compound is represented by Formula:wherein A represents a sterol; RT is an optionally substituted alkyl or an optionally substituted heteroalkyl; wherein each R is independently hydrogen or represents one or more substituents, each independently selected from halo, - NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, - CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, - NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl -NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, - CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6 alkyl), Ci-Ce mercaptoalkyl, -CONH(CI-C6 alkyl), -CON(CI-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted Cl -CIO alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof: wherein M represents a linker comprising at least one -N(R5)- group; wherein the linker is between 1 and 30 single C-C bonds long; wherein a, b, and R5 are as disclosed above; and wherein Z has a reactivity to a functional group selected from a thio group, an amino group, 1,3-nitrone, azide, a diene, succinimide, alpha-beta unsaturated carbonyl, alpha-beta unsaturated keto acid derivative, carbonyl, carboxy and active ester. In some embodiments, Z has a reactivity to a small molecule or to polymer comprising the functional group. Insome embodiments, Z has a reactivity to the functional group of the polymer of the invention.

[0116] In some embodiments, the compound is represented by Formula:, wherein b represents an integer being between 1 and 10; A represents a sterol; B represents at least one of an optionally substituted C3-C10 cycloalkyl, an optionally substituted C3-C10 heterocyclyl, an optionally substituted aryl, and an optionally substituted heteroaryl; RT is an optionally substituted alkyl or an optionally substituted heteroalkyl; and M and Z are as disclosed above.

[0117] In some embodiments, the compound is represented by Formula:disclosed above.

[0118] In some embodiments, the compound disclosed herein is a precursor of the conjugate of the invention. In some embodiments, the compound disclosed herein is configured to react with the polymer disclosed herein, so as to obtain the conjugate of the invention.

[0119] In some embodiments, the precursor is represented by Formula 5 A:

[0120] In some embodiments, the precursor is represented by Formula 11:

[0121] In some embodiments, the precursor is represented by Formula 12:wherein: m is an integer independently selected from 1 to 5; each XI is independently O, S, NR5, CRR or CH2; RT1 comprises an optionally substituted liner or branched alkyl; c is an integer independently selected from 0 to 10; LI is a bond, or a linker selected from -N- C(=O)-, -C(=O)N-, -S-S-, -S-C(=O), Y-(C0-10)alkyl-X-(C0-10)alkyl-Y, a cycloalkyl, a heterocyclyl and a click reaction product, or any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=0)-, -0C(=0)-, -0C(=0)0-, -OC(=S)O-, and -OC(=S)N-; the oligomer comprises between 2 and 15 repeating units.

[0122] In some embodiments, Z is or comprises an active ester (e.g., thio-ester, a pentofluorophenyl ester, a N-hydroxy succinimide ester, hydroxybenzotriazole ester, etc.); alpha, beta unsaturated carbonyl; alpha, beta unsaturated keto acid derivative; maleimide; 1,3-nitrone; thiol; amine; azide; alkyne; diene; alkene; tetrazole, or any combination thereof. In some embodiments, Z is or comprises an acyl halide, a chloroformate, an anhydride, an aldehyde, an epoxide, an isocyanate, an isothiocyanate, a maleimide, a carbonate (e.g. nitrophenyl carbonate), a sulfonyl chloride, iodoacetamide, an acyl azide, an imidoester, a vinyl sulfone, ortho-pyridyl-disulfide, or any combination thereof.

[0123] In some embodiments, Z is an active ester. The term “active ester” refers to ester with enhanced reactivity (fast kinetics) towards a nucleophilic attack, as compared to a regular alkyl ester. Active esters react with nucleophiles at room temperature, resulting in almost quantitative amide bond formation. The active esters have alcohol component inducing greater electron withdrawing effect, as compared to a regular alkyl ester. Withdrawal of electrons enhances the electrophilic character of the carbonyl carbon and thereby facilitates the formation of the tetrahedral intermediate with the nucleophile. Usually, the alcohol component of an active ester is a better leaving group, as compared to an alcohol of the regular alk l ester. As used herein, the term “active ester” refers to a storage stable compound.

[0124] The term “heteroalkyl” refers to an alkyl (i.e. linear, branched or cyclic alkyl chain) including one or more heteroatoms (e.g. O, S, N, and / or NH) within the backbone of the alkyl chain.

[0125] In some embodiments, Z is selected from an active ester (e.g., NHS ester), maleimide. and alpha, beta unsaturated keto acid (e.g., benzoyl acrylic acid anhydride). In some embodiment, the alpha, beta unsaturated keto acid or a derivative thereof is represented by the following Formula:wherein R” represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3- C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof; and wherein the wavy bond represents an attachment point to M.

[0126] In some embodiments, R” is an aryl or a substituted aryl. In some embodiments, R” is benzyl.

[0127] In some embodiments, the compound is presented by Formula 6:

[0128] In some embodiments, the compound is represented by Formula 6A:wherein R, R5, LI, Z, a, b, c, d and e are as disclosed herein above.

[0129] In some embodiments, LI is -N-C(=O), -C(=O)N or Y-(Co-io)alkyl-X-(Co- io)alkyl-Y.R'

[0130] In some embodiments,wherein R’ is as disclosed above, wherein n is an integer independently selected from 1 to 15.; and wherein the wavy bondrepresents attachment point to polymer (e.g., peptide) or the linker of the moiety of the invention In some embodiments, R’ is a hydrogen.

[0131] In some embodiments, the compound is represented by Formula 7 :c, d and e are as disclosed herein above.

[0132] In some embodiments, the compound is represented by Formula 7 A:d and e are as disclosed herein above.

[0133] In some embodiments, the compound is represented by Formula 10:

[0134] In some embodiments, the compound (precursor) is any one of compounds of Table A or of Table B.Table A:Table B:The MNM type (as assigned in Table 2) is highlighted in bold.

[0135] In another aspect there is provided a kit comprising the compound of the invention (i.e., precursor), and a polymer selected from (i) a polyamino acid; and (i) a polymer comprising a thio group, an amino group, 1,3 -nitrone, azide, diene, tetrazine, or any combination thereof.

[0136] In some embodiments, the polymer is within a composition (e.g., a solid composition, or a liquid composition such as a solution, a dispersion, or a suspension). In some embodiments, the composition comprises a plurality of nanoparticles (lipid nanoparticle, liposome, micelle, vesicle, nano-capsule, etc.), wherein each of the plurality of nanoparticles comprises the polymer.

[0137] In some embodiments, a molar ratio between the polymer and the precursor within the kit is about 1:1, about 1.5:1, about 5:1 and between about 5:1 and 1:1, between about 4:1 and 1:1, between about 3:1 and 1:1, between about 2:1 and 1:1, between 1.2:1 and 1:1, including any range in between.

[0138] In some embodiments, the kit further comprises instructions for reacting the polymer and the precursor under suitable conditions, to obtain the conjugate of the invention. In some embodiments, suitable conditions comprise conditions appropriate for reacting the polymer and the precursor of the invention, such as reaction time (e.g. between 0.1 and lOh, including any range between), a temperature (e.g. between 5 and 90C, including any range between).

[0139] In some embodiments, the kit further comprises a solvent. In some embodiments, the solvent is appropriate for dissolving the polymer and the precursor. In some embodiments, the polymer and the precursor have a solubility within the solvent of at least 0.5g / L, at least 10 g / L, or between 0.5 and 100 gZL, including any range between. In some embodiments, the solvent is selected from but not limited to an aqueous buffer, water, or an organic solvent.Pharmaceutical composition

[0140] In another aspect, there is provided a pharmaceutical composition, comprising the conjugate of the invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises one or more conjugate of the invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of one or more conjugate of the invention.

[0141] In some embodiments, the pharmaceutical composition consists essentially of the conjugate of the invention and the pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition consists essentially of the conjugate of the invention as the therapeutically active ingredient. In some embodiments, the pharmaceutical composition devoid of additional therapeutically active ingredients.

[0142] As used herein, the term "consists essentially of means that the composition, method, or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0143] In some embodiments, the pharmaceutical composition is for use in the treatment or prevention of a disease or a disorder, in a subject in need thereof. In some embodiments, the pharmaceutical composition is for use in the treatment of cancer.

[0144] In some embodiments, the pharmaceutically acceptable carrier is also referred to as an excipient or adjuvant. As used herein, the term “carrier,” “excipient,” or “adjuvant” refers to any component of a pharmaceutical composition that is not the active agent. As used herein, the term “pharmaceutically acceptable carrier” refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as com starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Some nonlimiting examples of substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present. Any non-toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein. Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the “Inactive Ingredient Guide,” U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, the contents of all of which are hereby incorporated by reference in their entirety. Examples of pharmaceutically acceptableexcipients, carriers, and diluents useful in the present compositions include distilled water, physiological saline, Hartmann solution, Ringer's solution, dextrose solution, Hank's solution, and DMSO. These additional inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990); Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990); and Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005), each of which is incorporated by reference herein in its entirety. The presently described composition may also be contained in artificially created structures such as liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum. Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally determined by considerations such as liposome size and stability in the blood. A variety of methods are available for preparing liposomes as reviewed, for example, by Coligan, J. E. et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0145] In some embodiments, the carrier may comprise, in total, from about 0.1% to about 99.99% by weight of the pharmaceutical compositions presented herein. In some embodiments, the carrier may comprise in total between 0.1 and 99.99%, between 0.1 and 50%, between 0.2 and 30%, between 0.1 and 70%, between 30 and 99.99%, between 50 and 99.99, by weight of the pharmaceutical compositions presented herein, including any range in between.

[0146] In some embodiments, the pharmaceutical composition as disclosed herein comprises a therapeutically effective amount of the conjugate of the invention. The term “a therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result in a subject. The exact dosage form and regimen would be determined by the physician according to the patient's condition.

[0147] As used herein, the term "pharmaceutically acceptable salt" refers to any nontoxic salt of the conjugate of the present invention that, upon administration to a subject, e.g., a human, is capable of providing, either directly or indirectly, a compound of this invention or a therapeutically active metabolite or residue thereof. For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0148] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.

[0149] Non-limiting examples of pharmaceutically acceptable salts include but are not limited to alkali metal salt, earth alkali metal salt, acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, halide (such as bromide, chloride, iodide, fluoride), bitartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, edetate, fumarate, gluconate, and lactate or any combination thereof.

[0150] Additional examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

[0151] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like.

[0152] In some embodiments, the conjugate of the invention is present in the pharmaceutical composition is of pharmaceutical grade purity, i.e., is characterized by a chemical purity of at least about 90%, at least about 95%, greater than 95%, or greater than 99%, and between 90 and 99.999%, between 90 and 95%, between 90 and 97%, between 95 and 99%, including any range in between, wherein the pharmaceutical composition is for use in the treatment of a disease or disorder in a subject in need thereof.Method

[0153] In one aspect there is provided a method for treating a disease or a condition within a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of the invention to the subject, thereby treating the disease or the condition.

[0154] In another aspect there is provided a method of internalizing the polymer of the invention (e.g. a polynucleic acid as disclosed herein, or a peptide) into a cell, comprising contacting the cell with the pharmaceutical composition of the invention, or with the conjugate of the invention. In some embodiments, the cell is an isolated cell. In some embodiments, the cell is a cultured cell. In some embodiments, the cell is a tissue cell. In some embodiments, the cell is a mammalian cell (e.g. a human cell). In some embodiments, the cell encompasses any cell of the subject. In some embodiments, the cell is attached to a support or is in a dispersion or suspension. In some embodiments, the cell is in contact with a cell medium.

[0155] In some embodiments, contacting comprises adding an effective amount of the conjugate or of the pharmaceutical composition to the cell, wherein the effective amount is so as to induce internalization of the therapeutic amount of the polymer into a cytosol of the cell. In some embodiments, contacting comprises adding the conjugate or the pharmaceutical composition to the cell medium in contact with the cell. In some embodiments, contacting comprises administering (locally or systemically) an effective amount of the conjugate or of the pharmaceutical composition to the subject. Cell internalization can be determined and quantified spectroscopically, such as by labelling the conjugate with a fluorescent probe and measuring the fluorescent signal within the cell (e.g. by ELISA reader, FACS, etc.).

[0156] In some embodiments, contacting comprises administering to the subject the pharmaceutical composition of the invention. In some embodiments, contacting comprisesadministering a therapeutically effective amount of the pharmaceutical composition to the subject.

[0157] In some embodiments, administering comprises systemic administration. In some embodiments, administering comprises a local administration. In some embodiments, administering comprises an intravenous administration.

[0158] In some embodiments, the method is for reducing at least one symptom associated with the disease or condition within a subject. In some embodiments, the subject is afflicted with a cell proliferation disease. In some embodiments, the disease is a cell proliferation disease. In some embodiments, the cell proliferation disease is cancer.

[0159] In some embodiments, the disease is selected from: retinal excitotoxicity, neuropathic pain, intraocular inflammation, a condition associated with cerebral ischemia / intracerebral hemorrhage, hearing loss, and acute sensorineural hearing loss caused by any one of: cochlear ischemia, semi-circular canal injury, cochlear implantation trauma, acute labyrinthitis, and aminoglycoside ototoxicity, including any combination thereof.Definitions

[0160] The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl. The term “alkyl” encompasses a linear, a branched or a cyclic hydrocarbon chain.

[0161] The term "alkenyl" describes an unsaturated alkyl, as defined herein, having at least two carbon atoms, between two to thirty carbon atoms, and at least one carbon-carbon double bond. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0162] The term "alkynyl", as defined herein, is an unsaturated alkyl having at least two carbon atoms, between two to thirty carbon atoms, and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0163] As used herein the term “C1-C6 alkyl” including any C1-C6 alkyl related compounds, is referred to any linear or branched alkyl chain comprising between 1 and 6, between 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, between 5 and 6, carbon atoms, including any range therebetween. In some embodiments, C1-C6 alkyl comprises any of methyl, ethyl, propyl, butyl, pentyl, iso-pentyl, hexyl, and tert-butyl or anycombination thereof. In some embodiments, C1-C6 alkyl as described herein further comprises an unsaturated bond, wherein the unsaturated bond is located at 1st, 2nd, 3rd, 4th, 5th, or 6th position of the C1-C6 alkyl.

[0164] The term “C1-C6 haloalkyl” refers to C1-C6 alkyl as described herein substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 halide atoms, wherein halide is selected from F, Br, Cl, and I, or a combination thereof.

[0165] As used herein, the terms “halogen”, "halo" and "halide", which are referred to herein interchangeably, describe an atom of a halogen, that is fluorine, chlorine, bromine, or iodine, also referred to herein as fluoride, chloride, bromide, and iodide.

[0166] The term “(C3-C10) cycloalkyl” is referred to an optionally substituted C3, C4, C5, C6, C7, C8, C9 or CIO ring. In some embodiments, (C3-C10) ring comprises optionally substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane, or cycloheptane.

[0167] In some embodiments, the term “hydroxy(Cl-C6 alkyl)” and the term “C1-C6 alkoxy” are used herein interchangeably and refer to C1-C6 alkyl as described herein substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hydroxy group(s), wherein the hydroxy group(s) is located at 1st, 2nd, 3rd, 4th, 5th, or 6th position of the C1-C6 alkyl, including any combination thereof.

[0168] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e. rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted, as indicated herein.

[0169] The term "alkoxy" describes both an O-alkyl and an -O-cycloalkyl group, as defined herein.

[0170] The term "aryloxy" describes an -O-aryl, as defined herein.

[0171] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0172] The term “hydroxyl” or "hydroxy" describes a -OH group.

[0173] The term "mercapto" or “thiol” describes a -SH group.

[0174] The term "thioalkoxy" describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein.

[0175] The term "thioaryloxy" describes both an -S-aryl and a -S-heteroaryl group, as defined herein.

[0176] The term “amino” describes a -NR’R” group, with R’ and R” as described herein.

[0177] The term “C3-C10 heterocyclyl” is referred to an optionally substituted C3, C4, C5, C6, C7, C8, C9 or CIO heterocyclic aromatic and / or aliphatic, or unsaturated ring, and describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen, and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino and the like.

[0178] The term "carboxy" or "carboxylate" describes a -C(O)OR' group, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon) or heterocyclyl (bonded through a ring carbon) as defined herein.

[0179] The term “carbonyl” describes a -C(O)R' group, where R' is as defined hereinabove.

[0180] The above-terms also encompass thio-derivatives thereof (thiocarboxy and thiocarbonyl).

[0181] The term “thiocarbonyl” describes a -C(S)R' group, where R' is as defined hereinabove.

[0182] A "thiocarboxy" group describes a -C(S)OR' group, where R' is as defined herein.

[0183] A "sulfinyl" group describes an -S(O)R' group, where R' is as defined herein.

[0184] A "sulfonyl" or “sulfonate” group describes an -S(O)2R' group, where R' is as defined herein.

[0185] A "carbamyl" or “carbamate” group describes an -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'.

[0186] A "nitro" group refers to a -NO2 group.

[0187] The term "amide" as used herein encompasses C-amide and N-amide.

[0188] The term "C-amide" describes a -C(O)NR'R" end group or a -C(O)NR'-linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0189] The term "N-amide" describes a -NR"C(O)R' end group or a -NR'C(O)- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0190] The term "carboxylic acid derivative" as used herein encompasses carboxy, amide, carbonyl, anhydride, carbonate ester, and carbamate.

[0191] A "cyano" or "nitrile" group refers to a -CN group.

[0192] The term "azo" or "diazo" describes an -N=NR' end group or an -N=N- linking group, as these phrases are defined hereinabove, with R' as defined hereinabove.

[0193] The term "guanidine" describes a -R'NC(N)NR"R"' end group or a -R'NC(N) NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

[0194] As used herein, the term “azide” refers to a -N3 group.

[0195] The term “sulfonamide” refers to a -S(O)2NR'R" group, with R' and R" as defined herein.

[0196] The term “phosphonyl” or “phosphonate” describes an -OP(O)-(OR')2 group, with R' as defined hereinabove.

[0197] The term “phosphinyl” describes a -PR'R" group, with R' and R" as defined hereinabove.

[0198] The term “alkylaryl” describes an alkyl, as defined herein, which substituted by an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0199] The term "heteroaryl" describes a monocyclic (e.g. C5-C6 heteroaryl ring) or fused ring (i.e. rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen, and sulfur and, in addition, having a completely conjugated pi-electron system. In some embodiments, the terms “heteroaryl” and “C5-C6 heteroaryl” are used herein interchangeably. Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazol, pyridine, pyrrole, oxazole, indole, purine, and the like.

[0200] As used herein, the terms “treatment” or “treating” of a disease, disorder, or condition encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition,reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life.

[0201] As used herein, the term “prevention” of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term "prevention" relates to a process of prophylaxis in which a subject is exposed to the presently described active ingredients prior to the induction or onset of the disease / disorder process. This could be done where an individual has a genetic pedigree indicating a predisposition toward occurrence of the disease / disorder to be prevented. For example, this might be true of an individual whose ancestors show a predisposition toward certain types of inflammatory disorders.

[0202] The term "suppression" is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to be realized. Thus, the cells of an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression.

[0203] Conversely, the term "treatment" refers to the clinical application of active agents to combat an already existing condition whose clinical presentation has already been realized in a patient.

[0204] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of, or any combination of items it conjoins.

[0205] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a”, “an” and “at least one” are used interchangeably in this application.

[0206] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0207] In the description and claims of the present application, each of the verbs, “comprise”, “include”, and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.

[0208] Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0209] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive.

[0210] Throughout this specification and claims, the word “comprise” or variations such as “comprises” or “comprising” indicate the inclusion of any recited integer or group of integers but not the exclusion of any other integer or group of integers.

[0211] As used herein, the term “consists essentially of’ or variations such as “consist essentially of’ or “consisting essentially of’ as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially change the basic or novel properties of the specified method, structure, or composition.

[0212] As used herein, the terms "comprises", "comprising", "containing", "having" and the like can mean "includes", "including", and the like; "consisting essentially of or "consists essentially" likewise has the meaning ascribed in U.S. patent law and the term is open- ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. In one embodiment, the terms "comprises" "comprising", and "having" are / is interchangeable with "consisting".

[0213] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0214] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation, or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.EXAMPLES

[0215] Generally, the nomenclature used herein, and the laboratory procedures utilized in the present invention include biochemical, cell biology and molecular biology techniques. Such techniques are thoroughly explained in the literature.

[0216] Non-limiting exemplary synthetic procedures of the conjugates of the invention are provided herein below.EXAMPLE 1Synthesis of Apo-Si-K-1011-2

[0217] Step 1: synthesis of 1011-5Scheme 1. Synthesis of 1011-5

[0218] Step 2: synthesis of 170A-6aApo-Si-K-1011-2Scheme 3: synthesis of Apo-Si-K1011-2

[0220] Exemplary precursors synthesized and successfully incorporated into exemplary conjugates are presented in Tables A and B above.EXAMPLE 2Synthesis of Apo-Si-K-1012 and Apo-Si-K-1021BOC2OScheme 4. Synthesis of Apo-Si-K-1012Apo-Si-K-1021Scheme 5. Synthesis of Apo-Si-K-1021,Scheme 5B. Synthesis of Apo-Si-K-1025Scheme 5C. Synthesis of Apo-Si-K-1033Scheme 5D. Synthesis of Apo-Si-K-1032PPh3, l2,.Apo-Si-K-1027Scheme 5E. Synthesis of Apo-Si-K-1027

[0221] The precursor of the invention is referred to herein as “MNM”.EXAMPLE 3

[0222] N-terminal MNM-JNKIStep 1: synthesis of compound 2Scheme 6. Synthesis of compound 2

[0223] Step 2: peptide synthesisPeptide synthesis was by done by standard Fmoc chemistry on a solid support using Dde side-chain protected Fmoc-Lysine. After finalizing the SPPS synthesis including N-terminal Fmoc deprotection, the Dde protecting group has been cleaved with hydrazine following by treating with Fmoc-Osu, so as to result in a peptide having Fmoc -protected lysine sidechain. Upon cleavage from the resin, the resulting peptide has been HPLC purified.Peptide sequence: NH2-ggdqsrpvqpflnlttprk(Fmoc)pr-C(=O)NH2 (SEQ ID NO: 1)

[0224] Step 3: conjugate synthesisScheme 7. Synthesis of N-terminal MNM- JNKI

[0225] To a solution of Compound 2 (11.4 mg, 11.4 umol) and Peptide (11.4 umol) in DMF (100 uL) was added DIEA (2.98 uL, 17.1 umol). The reaction mixture was stirred at 25 °C for 0.5 hrs. LC-MS showed that Compound 2 was consumed completely and one main peak with desired mass was detected.

[0226] Then TEA (200 uL) was added and stirred for 16 hrs. The reaction was monitored by LCMS. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to give N-terminal MNM- JNKI as a white solid.EXAMPLE 4 Lys-MNM-JNKI

[0227] Step 1: peptide synthesisPeptide synthesis was by done by standard Fmoc chemistry on a solid support using Boc side-chain protected Fmoc-Lysine. After finalizing the SPPS synthesis (without N-terminal Fmoc deprotection), the peptide has been cleaved from the resin and HPLC purified, so as to result in a peptide having Fmoc -protected N-terminus.Peptide sequence: Fmoc-NH-ggdqsrpvqpflnlttprkpr-C(=O)NH2 (SEQ ID NO: 1)

[0228] Step 2: conjugate synthesisScheme 8. Synthesis of Lys-MNM- JNKI

[0229] Step 2 has been performed as disclosed above.EXAMPLE 5MNM-CPP-JNKI

[0230] Step 1: conjugate synthesisPeptide synthesis was done by standard Fmoc chemistry on a solid support using Dde sidechain protected lysines, which have been Fmoc -protected on the solid support, as disclosed above.Peptide sequence: H2N-ggdqsrpvqpflnlttprkprpprrrqrrk(Fmoc)k(Fmoc)rg-C(=O)NH2 (SEQ ID NO: 2)

[0231] Step 2: conjugate synthesisScheme 9. Synthesis of MNM-CPP- JNKI

[0232] Step 2 has been performed as disclosed above.EXAMPLE 6C-terminal MNM-JNKI

[0233] Step 1: conjugate synthesisThe peptide was synthesized using standard Fmoc chemistry on a solid support (Rink amideMB HA Resin (0.1 mmol, 0.3 g, sub: 0.33 mmol / g)).Peptide sequence: dqsrpvqpflnlttprkprppcc (SEQ ID NO: 3)

[0234] Step 2: conjugate synthesisScheme 10. Synthesis of C-terminal MNM JNKI

[0235] All the peptide sequences mentioned herein have been synthesized using D amino acids.EXAMPLE 7 Viability test

[0236] The exemplary four conjugates of the invention were tested in a viability test. The conjugates comprise a JNK inhibitor (D-JNKI-1) and its effect on the cell viability was examined on B16 cells (murine melanoma) and Hela-GFP cells (human cervical cancer) based on an XTT-based assay (Biological Industries; #20-300-1000).

[0237] B 16 (8,000 cells / well) and Hela (5,000 cells / well) were plated in a 96-well flat bottom plate and grown in cell culture medium supplemented with 10% serum at 37°C / 5% CO2 overnight. Then the medium was replaced by reduced serum medium (Opti-MEM, Gibco; #31985070) and the cells were treated with the peptides mentioned in Tables 2 and 3 respectively (Table 3 summarizes the entire sequences used in experiments presented inFigs. 1-3). Stock solutions of all peptides were prepared in DMSO (stock solution cone. 1 mM), unless indicated otherwise. The day after treatment, XTT reagent was added to each well according to the manufacturer instructions and colorimetric results were measured by colorimetric read (Infinite M200 PRO; Tecan). The absorbance values were normalized to the respective control (vehicle), results are summarized in Figs. 1, 3 and Fig. 2 for B 16 and Hela cells, respectively.

[0238] Fig. 1 summarizes the viability test results on melanoma B16 cells. Control experiments indicate that CPP and D-JNKI- 1 up to 10 pM have a slight effect on the viability of the cells (up to 10%), when CPP and JNKI are Conjugated (CPP-JNKI), the viability decreases by additional 20%. When the cells were exposed to 25 pM of CPP-JNKI viability decreases to 25%. When the four conjugates of the invention were examined N-terminal MNM-JNKI, C-Terminal MNM-JNKI, Lys-MNM-JNKI and MNM-CPP-JNKI, results indicate that the attachment point within the peptide affects the reactivity of the inhibitor. When the conjugate is attached to the C-terminus of the peptide, the viability is equivalent to the CPP-JNKI. Whereas, attaching the JNKI to the N terminus shows a viability of 30%, and 2% for 5 pM and 10 pM respectively, indicating the conjugate enhances the JNKI activity. As for Lys-MNM-JNKI the viability decreases by more than half at 10 pM. The best results were achieved when the conjugate was attached to a CPP (MNM-CPP-JNKI) in which 50% and 0% viability were seen for 1 and 5 pM, respectively. IC50 values are summarized in Table 2 for each conjugate.

[0239] The inventors observed that a conjugate comprising a combination of CPP and the moiety of the invention (Molecular Nano-Motor; MNM) as the carrier is highly superior (more than 3 -fold higher activity, such as for # Pe 21) in terms of cellular delivery of the cargo (e.g. peptide) and induced cell mortality over a similar conjugate comprising the same MNM without CPP (#Pe 20). The tested conjugates of the invention (including #Nos. as assigned in Figure 3), as well as controls used in the experiment are summarized in Table 3. The structures of the MNMs used in the experiment are presented in Tables A and B. A graph summarizing the in-vitro results of the experiment is presented in Figures 1-3.Table 2: IC50 values of the different conjugates on melanoma B 16 cells and Hela cellsTable 3: tested conjugates of the invention and controls

[0240] As for Hela cells (Fig. 2), the same trend has been observed. Of note, MNM 1026:was completely inactive in-vitro.

[0241] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0242] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

CLAIMSWhat is claimed is: l. A conjugate comprising a polymer covalently bound to a moiety represented byFormula A’:including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof, wherein: a and b each independently represents an integer being between 1 and 10;A represents a sterol;RT is an optionally substituted alkyl or an optionally substituted heteroalkyl;L represents a linker comprising at least one -N(R5)- group, and wherein the linker is between 1 and 30 single C-C bonds long;R is hydrogen or represents one or more substituents, each independently selected from halo, -NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, - CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, - NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, - SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted Cl- C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), - CON(C1-C6 alkyl)2, -CO2H, -COR’, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, - OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6 alkyl), Ci-Ce mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, - OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof;a wavy bond represents an attachment point to the polymer; and wherein the polymer comprises a polyaminoacid.

2. The conjugate of claim 1, wherein said moiety is represented by Formula 1Am is an integer independently selected from 1 to 5; each Xi is independently O, S, NRs, CRR or CH2;RTI comprises an optionally substituted liner or branched alkyl;R5 is H or a straight or branched optionally substituted Cl - C5 alkyl, optionally comprising one or more heteroatoms; c is an integer independently selected from 0 to 10;LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-S-, -S-C(=O), Y-(Co- io)alkyl-X-(Co-io)alkyl-Y, a cycloalkyl, a heterocyclyl and a click reaction product, or any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, - NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and - OC(=S)N-; the oligomer comprises between 2 and 15 repeating units; andW represents (i) an amide, (ii) a click reaction product, or both.

3. The conjugate of claim 2, wherein the repeating unit is selected from: alkylene oxide, a natural or an unnatural amino acid derivative, an alpha-hydroxy carboxylic acid residue, and an amino group.

4. The conjugate of any one of claims 1 to 3, wherein LI is -N-C(=O), -C(=O)N, or Y- (Co-io)alkyl-X-(Co-io)alkyl- Y; an wherein at least one XI is CRR, and each R is independently hydrogen or represents one or more substituents, each independently selected from -NO2, -CN, -OR’, -OH, -C0NH2, -CONR’2, -CNNR’2, -CSNR’2, - CONH-OH, -C0NH-NH2, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, - SO2R’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH2, -NR’R’, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, -C02H, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, or a combination thereof.

5. The conjugate of any one of claims 2 to 4, wherein said moiety is represented by Formula 3:wherein d and e are integers each independently being between 1 and 10, wherein at least one XI is -O-.

6. The conjugate of any one of claims 2 to 5, wherein said click reaction product comprises any one of: succinimide-thioether; azide alkyne cycloaddition product; Diels Alder reaction product; inverse electron demand Diels Alder reaction product; dibenzyl cyclooctyne 1,3-nitrone cycloaddition product, or any combination thereof.

7. The conjugate of any one of claims 1 to 6, wherein said polymer is a peptide and wherein said peptide comprises a therapeutically affective amino acid sequence and further comprises a cell-penetrating peptide bound to the therapeutically affective amino acid sequence.

8. The conjugate of claim 7, wherein said moiety is bound to (i) the N-terminus of said peptide, or to the C-terminus of said peptide, (ii) to the C-terminal amino acid of said peptide, (iii) at least one of: an amino group and a thio group of an amino acid residue of said peptide, or any combination of (i)-(iii).

9. The conjugate of any one of claims 1 to 4, wherein said moiety is represented byFormula 4:wherein n is integer independently selected from 1 to 10; and wherein each Y1 and Y2 is absent or is independently selected from a cycloalkyl, a heterocyclyl, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, - OC(=O)O-, -OC(=S)O-, and -OC(=S)N-.

10. The conjugate of claim 9, wherein Y1 is -N-C(=O)-, and Y2 is -N-C(=O)- or - C(O=)O-.

11. The conjugate of any one of claims 1 to 10, wherein R5 is methyl.

12. The conjugate of any one of claims 1 to 11, wherein R is a halogen.

13. The conjugate of any one of claims 1 to 12, wherein said conjugate is selected from:

14. A compound, including any pharmaceutically acceptable salt, any hydrate, or any d compound is represented by Formula C:a and b each independently represents an integer being between 1 and 10;A represents a sterol;RT is an optionally substituted alkyl or an optionally substituted heteroalkyl;M represents a linker comprising at least one -N(R5)- group; and wherein the linker is between 1 and 30 single C-C bonds long;Z is a moiety having a reactivity to a functional group selected from a thio group, an amino group, 1,3 -nitrone, azide, a diene, tetrazine, succinimide, alpha-beta unsaturated carbonyl, alpha-beta unsaturated keto acid derivative, carbonyl and active ester, or any combination thereof;R is hydrogen or represents one or more substituents, each independently selected from is hydrogen or represents one or more substituents, each independently selected from halo, - NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, - CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, -NHCSR’, -NHCNR’, -NC(=O)OR’, - NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, -SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl -NR’2, C1-C6 alkyl-SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, - CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’,amino(Ci-C6 alkyl), Ci-Ce mercaptoalkyl, -C0NH(CI-C6 alkyl), -C0N(CI-C6 alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted Cl -CIO alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof;R5 is H or a straight or branched optionally substituted C 1 - C5 alkyl, optionally comprising one or more heteroatoms.

15. The compound of claim 14, wherein said compound is represented by Formulawherein: m is an integer independently selected from 1 to 5; each Xi is independently O, S, NR5, CRR or CH2;RTI comprises an optionally substituted liner or branched alkyl; c is an integer selected from 1 to 10;LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-C(=O), Y-(Co- io)alkyl-X-(Co-io)alkyl-Y, a cycloalkyl, a heterocyclyl and a click reaction product, including any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, - NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, - OC(=S)O-, -OC(=S)N-; the oligomer comprises between 2 and 15 repeating units.

16. The compound of claim 15, wherein LI is -N-C(=O), -C(=O)N, or Y-(C0- 10)alkyl-X-(C0-10)alkyl-Y; and wherein at least one XI is CRR, and each R is independently hydrogen or represents one or more substituents, each independently selected from -NO2, -CN, -OR’, -OH, -CONH2, -CONR’2, -CNNR’2, -CSNR’2, - CONH-OH, -C0NH-NH2, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, - SO2R’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH2, -NR’R’, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, -CO2H, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, or a combination thereof.

17. The compound of any of claims 14 to 16, wherein said compound is represented by Formula 7 :

18. The compound of any one of claims 14 to 16, wherein said compound is represented by Formula 8:wherein n is integer independently selected from 1 to 10; and wherein each Y 1 and Y2 are independently selected from a cycloalkyl, a heterocyclyl, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, -NC(=S)N-, -SO2-, -SO-, -SR’, - C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and -OC(=S)N-.

19. The compound of claim 18, wherein Y1 is -N-C(=O)-, and Y2 is -N-C(=O)- or - C(O=)O-.

20. The compound of any one of claims 14 to 19, wherein Z is selected from carboxy, active ester, carbonate, isocyanate, alpha-beta unsaturated keto compound, thioacetyl, and maleimide.

21. The compound of any of claims 14 to 20, wherein R is halo, and R5 is methyl.

22. The compound of any of claims 14 to 21, wherein the compound comprises any one of compounds of Table A.

23. The compound of any one of claims 14 to 22, wherein Z has reactivity to a polymer comprising said functional group; and wherein said compound is a precursor of said conjugate of any one of claims 1 to 13.

24. A pharmaceutical composition, comprising the conjugate of any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, comprising a therapeutically effective amount of said conjugate.

26. The pharmaceutical composition of claim 24 or 25, for use in the treatment or prevention of a disease in a subject.

27. The pharmaceutical composition of claim 26, wherein said disease is cancer.

28. A kit comprising said compound of any of claims 14 to 23, and a polymer selected from (i) a polyaminoacid; and (ii) a polymer comprising an amino acid and further comprising a thio group, an amino group, 1,3 -nitrone, azide, a diene, tetrazine, or any combination thereof.

29. The kit of claim 28, wherein a molar ratio between the polymer and the compound within the kit is about 1:1.

30. The kit of claim 28 or 29, wherein said kit further comprises instructions for reacting said polymer and said compound to obtain the conjugate of any one of claims 1 to 13.

31. The kit of any one of claims 28 to 30, wherein said kit further comprises a liquid carrier.

32. A method for treating a disease or condition within a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 24 or 25 to said subject, thereby treating said disease.

33. The method of claim 32, wherein said disease is a cell proliferation related disease.

34. A method for internalizing a polyaminoacid into a cell, comprising contacting said cell with the pharmaceutical composition of claim 24 or 25, thereby internalizing the peptide into the cell.

35. The method of claim 34, wherein said cell is a cancer cell.

36. A conjugate comprising a polymer covalently bound to a moiety represented by Formula B’:including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof, wherein: b represents an integer being between 1 and 10;A represents a sterol;B represents an optionally substituted C3-C10 heterocyclyl;RT is an optionally substituted alkyl or an optionally substituted heteroalkyl;L represents a linker being between 1 and 30 single C-C bonds long; a wavy bond represents an attachment point to the polymer; and wherein the polymer comprises a polyaminoacid.

37. The conjugate of claim 1, wherein said moiety is represented by Formula 9:, wherein: each X2 is independently N, or CR; each R is independently hydrogen or represents one or more substituents, each independently selected from halo, -NO2, -CN, -OR’, -OH, -C0NH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -C0NH-NH2, -NHCOR’, - NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, - SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl -SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -C02H, -COR’, -C02R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6alkyl), Ci-C6mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C 1 -C 10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof.

38. The conjugate of claim 37, wherein said moiety is represented by Formula 10:wherein: m is an integer independently selected from 1 to 5; each Xi is independently 0, S, NR5, CRR or CH2;RTI comprises an optionally substituted liner or branched alkyl; c is an integer independently selected from 0 to 10;LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-C(=O), Y-(Co-io)alkyl- X-(Co-io)alkyl-Y, a cycloalkyl, a heterocyclyl and a click reaction product, or any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, - NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and - OC(=S)N-; the oligomer comprises between 2 and 15 repeating units; and W represents (i) an amide, (ii) a click reaction product, or both.

39. The conjugate of claim 38, wherein LI is a bond; an wherein at least one XI is CRR, and each R is independently hydrogen or represents one or more substituents, each independently selected from -NO2, -CN, -OR’, -OH, -CONH2, -CONR’2, -CNNR’2, - CSNR’ 2, -CONH-OH, -CONH-NH2, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, - NC(=S)NR’, -SO2R’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, -NH2, -NR’R’, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO2H, -OC(=O)OR’, -OC(=O)NR’, - OC(=S)OR’, -OC(=S)NR’, or a combination thereof.

40. A compound, including any pharmaceutically acceptable salt, any hydrate, or any solvate thereof; wherein said compound is represented by Formula D:A / O RZ M bTincluding any pharmaceutically acceptable salt, any hydrate, or any solvate thereof, wherein: b represents an integer being between 1 and 10;A represents a sterol;B represents an optionally substituted C3-C10 heterocyclyl;RT is an optionally substituted alkyl or an optionally substituted heteroalkyl;M represents a linker being between 1 and 30 single C-C bonds long;Z is a moiety having a reactivity to a functional group selected from a thio group, an amino group, 1,3-nitrone, azide, a diene, tetrazine, succinimide, alpha-beta unsaturated carbonyl, alpha-beta unsaturated keto acid derivative, carbonyl and active ester, or any combination thereof.

41. The compound of claim 40, represented by Formula 11:each X2 is independently N, or CR; each R is independently hydrogen or represents one or more substituents, each independently selected from halo, -NO2, -CN, -OR’, -OH, -CONH2, HCONH-, oxo, carbonyl, amino, imino, thioxo, phosphate (i.e. -OPO(OR’)2), phosphonate, phosphine, phosphite, -CONR’2, -CNNR’2, -CSNR’2, -CONH-OH, -CONH-NH2, -NHCOR’, - NHCSR’, -NHCNR’, -NC(=O)OR’, -NC(=O)NR’, -NC(=S)OR’, -NC(=S)NR’, - SO2R’, -SOR’, -SR’, -SO2OR’, -SO2N(R’)2, -NHNR’2, -NNR’, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR’R’, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(Cl-C6 alkyl), hydroxy(Cl-C6 alkoxy), alkoxy(Cl-C6 alkyl), alkoxy(Cl-C6 alkoxy), C1-C6 alkyl-NR’2, C1-C6 alkyl -SR’, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -COR’, -CO2R’, -OCOR’, -OCOR’, -OC(=O)OR’, -OC(=O)NR’, -OC(=S)OR’, -OC(=S)NR’, amino(Ci-C6alkyl), Ci-C6mercaptoalkyl, -CONH(CI-C6alkyl), -CON(CI-C6alkyl)2, -CO2H, -CO2R, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, alkyl-aryl, alkyl-heteroaryl or a combination thereof; each R’ independently represents hydrogen, or is selected from the group comprising optionally substituted C 1 -C 10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or a combination thereof.

42. The compound of claim 41, represented by Formula 12:wherein: m is an integer independently selected from 1 to 5; each Xi is independently O, S, NRs, CRR or CH2;RTI comprises an optionally substituted liner or branched alkyl; c is an integer independently selected from 0 to 10;LI is a bond, or a linker selected from -N-C(=O)-, -C(=O)N-, -S-C(=O), Y-(Co-io)alkyl- X-(Co-io)alkyl-Y, a cycloalkyl, a heterocyclyl and a click reaction product, or any combination thereof; each X and Y is absent or is independently selected from a heteroatom, an oligomer, a click reaction product, -CONR’-, -CNNR’-, -CSNR’-, -NC(=O)O-, -NC(=S)O-, - NC(=S)N-, -SO2-, -SO-, -SR’, -C(=O)-, -OC(=O)-, -OC(=O)O-, -OC(=S)O-, and - OC(=S)N-; the oligomer comprises between 2 and 15 repeating units.

43. The compound of any one of claims 40 to 42, wherein the compound comprises any one of compounds of Table B.

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