Polypeptide conjugates for intracellular delivery of stapled peptides

A polypeptide conjugate comprising a cyclic cell penetrating peptide (cCPP) and a stapled peptide having a structure according to Formula IA:

• wherein:
• the stapled peptide comprises U, Y1, Y2, X, Z, J, Z′ or a combination thereof and a staple;
• each of X and Z, at each instance, are independently an amino acid;
• U, at each instance and when present, is independently an amino acid;
• a is a number in the range of from 0 to 500;
• c is 3, 6, or 10;
• d is a number in the range of from 1 to 500;
• Y1 is an amino acid which has a side chain which forms a first bonding group (b1) to the staple;
• Y2 is an amino acid which has a side chain which forms a second bonding group (b2) to the staple;
• cCPP is a cyclic peptide comprising about 4 to about 13 amino acids, wherein the about 4 to about 13 amino acids include at least two arginines and at least two amino acids with hydrophobic side chains;
• wherein:
• the staple comprises an amide, alkylene substituted with an oxo or N-oxide, or an aryl;
• the linker comprises at least one amino acid, alkylene, alkenylene, alkynylene, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, heteroaryl, ether, or a combination thereof, each of which are optionally substituted;
• and
• each of b1 and b2 are independently thioether, disulfide, amide, ester, or ether.