Cell penetrating peptides and methods of making and using thereof

Abstract

Disclosed herein are compounds having activity as cell penetrating peptides. In some examples, the compounds can comprise a cell penetrating peptide moiety and a cargo moiety. The cargo moiety can comprise one or more detectable moieties, one or more therapeutic moieties, one or more targeting moieties, or any combination thereof. In some examples, the cell penetrating peptide moiety is cyclic. In some examples, the cell penetrating peptide moiety and cargo moiety together are cyclic. In some examples, the cell penetrating peptide moiety is cyclic and the cargo moiety is appended to the cyclic cell penetrating peptide moiety structure. In some examples, the cargo moiety is cyclic and the cell penetrating peptide moiety is cyclic, and together they form a fused bicyclic system.

1 - 21 . (canceled) 
     
     
         22 . A compound comprising a cyclic peptide, the cyclic peptide comprising 6-12 amino acids;
 wherein at least two amino acids are phenylalanine and at least two amino acids are arginine; and   wherein two arginines are not consecutive and the two non-consecutive arginines are separated by an intervening amino acid, and wherein the two non-consecutive arginines have the same chirality and the intervening amino acid does not have the chirality of the two arginines.   
     
     
         23 . The compound of  claim 22 , further comprising at least one amino acid comprising a hydrophobic aromatic residue. 
     
     
         24 . The compound of  claim 23 , wherein the amino acid comprising a hydrophobic aromatic residue is naphthylalanine, tryptophan, or tyrosine. 
     
     
         25 . The compound of  claim 22 , wherein the cyclic peptide comprises at least three arginines. 
     
     
         26 . The compound of  claim 22 , wherein the cyclic peptide comprises at least four arginines. 
     
     
         27 . The compound of  claim 22 , further comprising a cargo conjugated to the cyclic peptide. 
     
     
         28 . The compound of  claim 27 , wherein the cargo is conjugated to an amino group, side chain of an amino group, or carboxylate group of an amino acid of the cyclic peptide. 
     
     
         29 . The compound of  claim 22 , wherein the cyclic peptide comprises Formula IIa, IIb, or IIc: 
       
         
           
           
               
               
           
         
         wherein:
 m, n and p are independently selected from 0 and 1; 
 AA 1 , AA 2 , AA 3 , AA 4 , AA 5 , AA 6 , AA 7 , AA 8 , and AA 9  are each independently an amino acid; and 
 the cargo comprises a therapeutic moiety. 
 
       
     
     
         30 . The compound of  claim 27 , wherein the cargo is a nucleic acid, and enzyme or antibody. 
     
     
         31 . The compound of  claim 29 , wherein the cargo is a nucleic acid, and enzyme or antibody. 
     
     
         32 . A method for delivering a cargo to cytoplasm of a cell, comprising administering at least one compound of  claim 29 , thereby delivering the cargo to the cytoplasm of the cell. 
     
     
         33 . A method for delivering a cargo to cytoplasm of a cell, comprising administering at least one compound, thereby delivering the cargo to the cytoplasm of the cell, wherein the compound is of formula IIA, IIb, or IIc 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 m, n, and p are independently selected from 0 and 1, 
 AA 1  is phenylalanine, 
 AA 2  is phenylalanine, 
 AA 3  is naphthylalanine, 
 AA 4  is arginine, 
 AA 5  is arginine, 
 AA 6  is arginine, 
 at least four consecutive amino acids have alternating chirality, and 
 the cargo comprises a detectable moiety, a therapeutic moiety, a targeting moiety or a combination thereof. 
 
       
     
     
         34 . The method of  claim 33 , wherein:
 m is 0;   n and p are each 1;   AA 8  is arginine; and   AA 9  is glutamine.   
     
     
         35 . The method of  claim 34 , wherein the compound is of formula (IIa). 
     
     
         36 . The method of  claim 34 , wherein the compound is of formula (IIb). 
     
     
         37 . The method of  claim 34 , wherein the compound is of formula (IIc). 
     
     
         38 . The method of  claim 34 , wherein the therapeutic moiety is a therapeutic protein. 
     
     
         39 . The method of  claim 38 , wherein the therapeutic protein comprises an enzyme. 
     
     
         40 . The method of  claim 38 , wherein the therapeutic protein comprises an antibody or nucleic acid.