Amino acid-, peptide- and polypeptide-lipids, isomers, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-10086013-B2
Application number	US-201615340082-A
Country	US
Kind code	B2
Filing date	Nov 1, 2016
Priority date	Oct 27, 2011
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

Described herein are compounds and compositions characterized, in certain embodiments, by conjugation of various groups, such as lipophilic groups, to an amino or amide group of an amino acid, a linear or cyclic peptide, a linear or cyclic polypeptide, or structural isomer thereof, to provide compounds of the present invention, collectively referred to herein as “APPLs”. Such APPLs are deemed useful for a variety of applications, such as, for example, improved nucleotide delivery. Exemplary APPLs include, but are not limited to, compounds of Formula (I), (II), (III), (IV), (V), and (VI), and salts thereof, as described herein:

wherein m, n, p, R′, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , Z, W, Y, and Z are as defined herein.

First claim

What is claimed is:

1. A method of delivering a polynucleotide to a cell, the method comprising contacting a composition comprising a polynucleotide and a compound of Formula (III):

or salt thereof, with the cell under conditions sufficient to facilitate delivery of the polynucleotide into the interior of the cell;
wherein:
p is 1;
each instance of Q is O;
each instance of R 1 is independently hydrogen, alkyl, or a group of formula (iv);
provided at least one instance of R 1 is a group of formula:

L is alkylene;
R 6 and R 7 are each independently hydrogen, alkyl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii);
each instance of R 2 is independently hydrogen, alkyl, a nitrogen protecting group, or a group of the formula (i), (ii), or (iii);
Formulae (i), (ii), and (iii) are:

wherein each instance of formula (i) is independently formula (i-a) or formula (i-b):

each instance of R′ is independently hydrogen or alkyl;
X is O, S, or NR X , wherein R X is hydrogen, or a nitrogen protecting group;
Y is O;
R P is hydrogen, alkyl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and
R L is C 6-50 alkyl,
provided that at least one instance of R 2 , R 6 , or R 7 is a group of the formula (i), (ii), or (iii);
wherein each alkyl and alkylene is independently unsubstituted or substituted at one or more positions with a group selected from halogen, —CN, —NO 2 , —OH, —OR aa , —N(R bb ) 2 , —N(R bb ) 3 + X − , —N(OR cc )R bb , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , —NR bb C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —OC(═NR bb )R aa , —OC(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —OC(═NR bb )N(R bb ) 2 , —NR bb C(═NR bb )N(R bb ) 2 , C 3-14 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 groups selected from halogen, —OH, —OR ee , and C 1-50 alkyl;
or two geminal hydrogens on a carbon atom are replaced with the group ═O;
each instance of R aa is, independently, selected from C 1-50 alkyl;
each instance of R bb is, independently, selected from hydrogen, and C 1-50 alkyl;
each instance of R ee is, independently, selected from C 1-50 alkyl, and C 3-10 carbocyclyl;
wherein X − is a counterion.

2. The method of claim 1 , wherein at least one instance of R 2 is hydrogen.

3. The method of claim 1 , wherein each instance of R 1 is a group of formula (iv).

4. The method of claim 1 , wherein the group of formula (iv) is of formula:

wherein q is an integer between 1 and 50, inclusive.

5. The method of claim 4 , wherein the group of formula (iv) is of formula:

wherein q is an integer between 1 and 10, inclusive.

6. The method of claim 5 , wherein q is 4.

7. The method of claim 1 , wherein the compound is selected from the group consisting of:

and salts thereof,
wherein:
R 1 is selected from the group consisting of —H, —CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH(CH 3 ) 2 ,

provided at least one R 1 is a group of formula:

8. The method of claim 7 , wherein at least one instance of R 6 or R 7 is a group of the formula (i), (ii), or (iii).

9. The method of claim 1 , wherein the compound is selected from the group consisting of:

and salts thereof.

10. The method of claim 1 , wherein the compound is selected from the group consisting of:

and salts thereof.

11. The method of claim 10 , wherein the compound is:

or salt thereof.

12. The method of claim 1 , wherein the composition further comprises cholesterol.

13. The method of claim 1 , wherein the composition further comprises a PEGylated lipid.

14. The method of claim 1 , wherein the composition further comprises a phospholipid.

15. The method of claim 1 , wherein the composition further comprises an apolipoprotein.

16. The method of claim 1 , wherein the polynucleotide is RNA.

17. The method of claim 16 , wherein the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.

18. The

Assignees

• Massachusetts Inst Technology

Inventors

• Dong Yizhou
• Love Kevin Thomas
• Langer Robert S
• Anderson Daniel Griffith
• Chen Delai
• Chen Yi
• Vegas Arturo Jose
• Alabi Akinleye C
• Zhang Yunlong

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title