Modified therapeutic agents, stapled peptide lipid conjugates, and compositions thereof
Methods and compositions are provided for extending the half-life of a therapeutic agent. A modified therapeutic agent (mTA) comprises a therapeutic agent, a staple, and a half-life extending molecule. The mTAs disclosed herein may be used to treat a disease or a condition in a subject in need thereof.
1. A modified therapeutic agent (mTA) comprising a therapeutic agent comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 30-32 and 35-53, a staple, and a half-life extending molecule, wherein the therapeutic agent is covalently attached to the staple via two amino acid residues in the therapeutic agent; the half-life extending molecule is covalently attached to the staple; and the half-life of the mTA is longer than the half-life of the therapeutic agent alone.
2. The mTA of claim 1 , wherein the half-life extending molecule comprises a lipid, a polyglycol region selected from
wherein m and n are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or a combination thereof.
3. The mTA of claim 2 , wherein the lipid is selected from a group consisting of sterols, bile acids, vitamin E, fatty di-acids, fatty acids, fatty amides, fatty amines, fatty alcohols, and derivatives thereof.
4. The mTA of claim 1 , wherein at least one of the two amino acid residues is an amino acid addition or substitution on the therapeutic agent.
5. The mTA of claim 1 , wherein each of the two amino acid residues is cysteine.
6. The mTA of claim 1 , wherein the staple comprises a group selected from:
wherein
each X is independently selected from O, NH, and S;
each Y is independently selected from N and CH;
each Z is independently selected from N and CH;
each R 8 and R 9 is independently H, —C(O)(alkyl), or comprises the half-life extending molecule;
each R 10 and R 11 is independently oxo or comprises the half-life extending molecule;
R 12 is independently hydroxy, alkoxy, or comprises the half-life extending molecule;
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17;
b is 1, 2, 3, 4, 5, or 6; and
c is 1 or 2.
7. The mTA of claim 6 , wherein the half-life extending molecule comprises a lipid, a polyglycol region selected from
wherein m and n are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or a combination thereof.
8. The mTA of claim 7 , wherein the half-life extending molecule comprises a lipid and a polyglycol region selected from
wherein m and n are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
9. The mTA of claim 8 , wherein the lipid is selected from a group consisting of sterols, bile acids, vitamin E, fatty di-acids, fatty acids, fatty amides, fatty amines, fatty alcohols, and derivatives thereof.
10. The mTA of claim 1 , wherein the half-life of the mTA is 5-fold longer than the half-life of the therapeutic agent alone.
11. A pharmaceutical composition comprising the mTA of claim 1 and a pharmaceutically acceptable excipient.
12. The mTA of claim 6 , wherein the staple comprises:
wherein
R 12 is independently hydroxy, alkoxy, or comprises the half-life extending molecule; and
cis 1 or 2.
13. The mTA of claim 1 , wherein the staple covalently attached to the half-life extending molecule is selected from the group consisting of: