Stapled and stitched polypeptides and uses thereof
The present invention provides stapled polypeptides of the Formulae (I) and (VI): (I) (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 polypeptide comprising a stapled α-helix having the structure of Formula (I):
or a pharmaceutically acceptable salt thereof; wherein:
represents a single bond or a double bond;
each of R 2a and R 2b is, independently, unsubstituted alkyl; unsubstituted heteroalkyl; unsubstituted carbocyclyl; unsubstituted heterocyclyl;
each of R 3a and R 3b is, independently, unsubstituted alkylene; unsubstituted heteroalkylene; unsubstituted carbocyclylene; or unsubstituted heterocyclylene; or optionally R 2a and R 3a are joined to form a ring; or optionally R 2b and R 3b are joined to form a ring;
L 1 is a bond, unsubstituted C 1-10 alkylene, or —C(═O)OR L1 —;
L 2 is a bond, unsubstituted C 1-10 alkylene, or —C(═O)OR L2 —; provided that when neither R 2a and R 3a nor R 2b and R 3b forms a ring, L 1 is —C(═O)OR L1 — or L 2 is —C(═O)OR L1 —;
each of R L1 and R L2 is, independently, C 1-10 alkylene;
each instance of X AA is, independently, an amino acid; and
m is 3 or 6.
2. The polypeptide of claim 1 , wherein the stapled α-helix has the structure of Formula (II):
or a pharmaceutically acceptable salt thereof; wherein:
each of X 1 and X 2 is, independently, a bond, —CH 2 —, or —NH—, provided that at least one of X 1 and X 2 is —NH—;
and each of j and k is, independently, an integer between 0 and 10, inclusive.
3. The polypeptide of claim 2 , wherein the stapled α-helix has the structure of Formula (II-a):
or a pharmaceutically acceptable salt thereof.
4. The polypeptide of claim 2 , wherein the stapled α-helix has the structure of Formula (II-b) or (II-c):
or a pharmaceutically acceptable salt thereof; wherein each of g and h is, independently, zero or an integer between 1 and 10, inclusive.
5. The polypeptide of claim 1 , wherein the stapled α-helix has the structure of Formula (III) or Formula (IV):
or a pharmaceutically acceptable salt thereof;
wherein:
each of X 1 and X 2 is, independently, a bond, —CH—, —CH 2 —, —N—, or —NH—; and
each of j, k, j1, and k1 is, independently, 0, 1, or 2.
6. The polypeptide of claim 5 , wherein the stapled α-helix has the structure of Formula (III-a):
or a pharmaceutically acceptable salt thereof.
7. The polypeptide of claim 5 , wherein the stapled α-helix has the structure of Formula (III-b):
or a pharmaceutically acceptable salt thereof.
8. The polypeptide of claim 5 , wherein the stapled α-helix has the structure of Formula (III-c):
or a pharmaceutically acceptable salt thereof.
9. The polypeptide of claim 5 , wherein the stapled α-helix has the structure of Formula (IV-a):
or a pharmaceutically acceptable salt thereof.
10. The polypeptide of claim 5 , wherein the stapled α-helix has the structure of Formula (IV-b):
or a pharmaceutically acceptable salt thereof.
11. The polypeptide of claim 5 , wherein the stapled α-helix has the structure of Formula (IV-c):
or a pharmaceutically acceptable salt thereof.
12. The polypeptide of claim 1 , wherein the stapled α-helix has the structure of Formula (V):
or a pharmaceutically acceptable salt thereof;
wherein each of X 1 and X 2 is, independently, a bond, —CH—, —CH 2 —, —N—, or —NH—; and
each of i, k, j1, and k1 is, independently, 0, 1, or 2.
13. The polypeptide of claim 1 , wherein the stapled α-helix has the structure of Formula (V-a), (V-b), or (V-c):
or a pharmaceutically acceptable salt thereof,
wherein each of g and h is, independently, zero or an integer between 1 and 10, inclusive; and
each of j, j 1 , k 1 , and k is, independently, 0, 1, or 2.
14. The polypeptide of claim 1 , wherein the stapled α-helix has the structure of Formula (V-d):
or a pharmaceutically acceptable salt thereof,
wherein each of g and h is, independently, zero or an integer between 1 and 10, inclusive; and
each of j, j 1 , k 1 , and k is, independently, 0, 1, or 2.
15. A polypeptide comprising a stitched α-helix having the structure of Formula (VI):
or a pharmaceutically acceptable salt thereof;
wherein:
each instance of , independently, represents a single bond, a double bond, or a triple bond;
each of R 2a and R 2b is, independently, unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; unsubstituted carbocyclyl; unsubstituted heterocyclyl;
each of R 3a and R 3b is, independently, unsubstituted alkylene; unsubstituted heteroalkylene; unsubstituted carbocyclylene; or unsubstituted heterocyclylene; or optionally R 2a and R 3a are joined to form a ring; or optionally R 2b and R 3b are joined to form a ring;
L 1 is a bond, unsubstituted C 1-10 alkylene, or —C(═O)OR L1 —;
L 2 is a bond, unsubstituted C 1-10 alkylene, or —C(═O)OR L2 —; each of R L1 and R L2 is, independently, optionally substituted C 1-10 alkylene;
each instance of X AA is, independently, an amino acid;
each of m and s is, independently, 3 or 6;
each of y, and z is, independently, an integer between 1 and 10, inclusive.
16. The polypeptide of claim 15 , wherein the stitched α-helix has the structure of Formula (VII), (VIII), (IX), or (X):
or a pharmaceutically acceptable salt thereof,
wherein each of X 1 and X 2 is, independently, a bond, —CH—, —CH 2 —, —N—, or —NH—; and
each of j, j 1 , k 1 , and k is, independently, 0, 1, or 2.
17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.