Stapled and stitched polypeptides and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/12
A61K-038/00
C07K-005/00
C07K-007/00
C07K-016/00
C07K-017/00
C07K-007/08
C07K-001/04
C07K-007/06
C07D-205/04
C07D-207/16
C07K-001/113
출원번호
US-0775315
(2014-03-13)
등록번호
US-10081654
(2018-09-25)
국제출원번호
PCT/US2014/025544
(2014-03-13)
국제공개번호
WO2014/159969
(2014-10-02)
발명자
/ 주소
Verdine, Gregory L.
Hilinski, Gerard
출원인 / 주소
President and Fellows of Harvard College
대리인 / 주소
Clark & Elbing LLP
인용정보
피인용 횟수 :
0인용 특허 :
74
초록▼
The present invention provides stapled polypeptides of the Formulae (I) and (VI): (I) (VI) and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides meth
The present invention provides stapled polypeptides of the Formulae (I) and (VI): (I) (VI) and salts thereof; wherein the groups ; R1a, R1b, R1c, R2a, R3a, R2b, R3b, R4a, R4b, RA, RZ, L1a, L1b, L2, L3, XAA, 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.
대표청구항▼
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 R2a and R2b is, independently, unsubstituted alkyl; unsubstituted heteroalkyl; unsubstituted carbocyclyl; unsub
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 R2a and R2b is, independently, unsubstituted alkyl; unsubstituted heteroalkyl; unsubstituted carbocyclyl; unsubstituted heterocyclyl;each of R3a and R3b is, independently, unsubstituted alkylene; unsubstituted heteroalkylene; unsubstituted carbocyclylene; or unsubstituted heterocyclylene; or optionally R2a and R3a are joined to form a ring; or optionally R2b and R3b are joined to form a ring;L1 is a bond, unsubstituted C1-10 alkylene, or —C(═O)ORL1—;L2 is a bond, unsubstituted C1-10 alkylene, or —C(═O)ORL2—; provided that when neither R2a and R3a nor R2b and R3b forms a ring, L1 is —C(═O)ORL1— or L2 is —C(═O)ORL1—;each of RL1 and RL2 is, independently, C1-10 alkylene;each instance of XAA is, independently, an amino acid; andm 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 X1 and X2 is, independently, a bond, —CH2—, or —NH—, provided that at least one of X1 and X2 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 X1 and X2 is, independently, a bond, —CH—, —CH2—, —N—, or —NH—; andeach 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 X1 and X2 is, independently, a bond, —CH—, —CH2—, —N—, or —NH—; andeach 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; andeach of j, j1, k1, 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; andeach of j, j1, k1, 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 R2a and R2b is, independently, unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; unsubstituted carbocyclyl; unsubstituted heterocyclyl;each of R3a and R3b is, independently, unsubstituted alkylene; unsubstituted heteroalkylene; unsubstituted carbocyclylene; or unsubstituted heterocyclylene; or optionally R2a and R3a are joined to form a ring; or optionally R2b and R3b are joined to form a ring;L1 is a bond, unsubstituted C1-10 alkylene, or —C(═O)ORL1—;L2 is a bond, unsubstituted C1-10 alkylene, or —C(═O)ORL2—; each of RL1 and RL2 is, independently, optionally substituted C1-10 alkylene;each instance of XAA 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 X1 and X2 is, independently, a bond, —CH—, —CH2—, —N—, or —NH—; andeach of j, j1, k1, and k is, independently, 0, 1, or 2. 17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.
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이 특허에 인용된 특허 (74)
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