Stapled and stitched polypeptides and uses thereof
The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R 1a , R 1b , R 1c , R 2a , R 3a , R 2b , R 3b , R 4a , R 4b , R A , R Z , L 1a , L 1b , L 2 , L 3 , X AA , v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.
1. A stapled peptide comprising a staple, wherein the staple comprises a carbamate moiety or a tertiary amine moiety,
wherein the stapled peptide comprises a residue of an amino acid of Formula (A):
or a salt thereof,
wherein:
R A is hydrogen;
R 1 is hydrogen, acyl, substituted or unsubstituted C 1-6 alkyl, or an amino protecting group;
R 2a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl;
R 3a is substituted or unsubstituted alkylene, unsubstituted heteroalkylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted heterocyclylene; or optionally R 2a and R 3a are joined to form a ring;
L 1 is a bond, substituted or unsubstituted C 1-10 alkylene, or —C(═O)OR L1 —;
R L1 is optionally substituted C 1-10 alkylene;
R B is hydrogen; and
wherein the residue of an amino acid of Formula (A) forms a staple with another amino acid residue.
2. The stapled peptide of claim 1 , wherein the staple comprises a carbamate moiety.
3. The stapled peptide of claim 2 , wherein the staple comprises two carbamate moieties.
4. The stapled peptide of claim 2 , wherein the staple is prepared using an amino acid selected from
and an amino acid without a carbamate moiety.
5. The stapled peptide of claim 2 , wherein the staple is prepared using two amino acids selected from
and analogs thereof containing additional methylene units.
6. The stapled peptide of claim 2 , wherein the cross-linking amino acids of the staple are located at positions i and i+4.
7. The stapled peptide of claim 2 , wherein the cross-linking amino acids of the staple are located at positions i and i+7.
8. The stapled peptide of claim 1 , wherein in Formula (A) is a double bond.
9. The stapled peptide of claim 8 , wherein R 3a is substituted or unsubstituted heteroalkylene containing at least one nitrogen.
10. The stapled peptide of claim 9 , wherein R 3a is —(CH 2 ) j —NR 1 —, wherein j is an integer between 1-10, inclusive.
11. The stapled peptide of claim 10 , wherein L 1 is —C(═O)OR L1 —, wherein R L1 is optionally substituted C 1-10 alkylene.
12. The stapled peptide of claim 11 , wherein R L1 is —(CH 2 ) g1 —, wherein g1 is an integer between 1 and 10 inclusive.
13. The stapled peptide of claim 9 , wherein L 1 is —C(═O)OR L1 —, wherein R L1 is optionally substituted C 1-10 alkylene.
14. The stapled peptide of claim 13 , wherein R L1 is —(CH 2 ) g1 —, wherein g1 is an integer between 1 and 10 inclusive.
15. The stapled peptide of claim 8 , wherein R 2a and R 3a are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C 3-6 heterocyclyl containing at least one nitrogen atom.
16. The stapled peptide of claim 1 , wherein in Formula (A) is a triple bond.
17. The stapled peptide of claim 1 , wherein the amino acid of Formula (A) is of Formula (D):
or a salt thereof,
wherein:
X 1 is CR 5 or N;
wherein R 5 is independently hydrogen, halogen, —NO 2 , —OH, —CN, or C 1-6 alkyl; and
each of j and j1 is independently an integer between 1 and 10, inclusive.
18. The stapled peptide of claim 17 , wherein L 1 is —C(═O)OR L1 —, wherein R L1 is optionally substituted C 1-10 alkylene.
19. The stapled peptide of claim 18 , wherein R L1 is —(CH 2 ) g1 —, wherein g1 is an integer between 1 and 10 inclusive.
20. The stapled peptide of claim 18 , wherein j1 is 1.
21. The stapled peptide of claim 20 , wherein j is 1.
22. The stapled peptide of claim 20 , wherein j is 2.
23. The stapled peptide of claim 17 , the amino acid of Formula (A) is
or a salt thereof, wherein g1 is an integer between 1 and 10, inclusive.
24. The stapled peptide of claim 1 , wherein the amino acid of Formula (A) is selected from