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

Patent metadata

Field	Value
Publication number	US-11458158-B2
Application number	US-202016867291-A
Country	US
Kind code	B2
Filing date	May 5, 2020
Priority date	Oct 27, 2011
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

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′, R1, R2, R3, R4, R5, R8, Z, W, Y, and Z are as defined herein.

First claim

What is claimed is:

1. A composition comprising a polynucleotide, and a compound of Formula (III):

or salt thereof, 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, or alkyl, an oxygen protecting group; 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 bb is, independently, selected from C 1-50 alkyl and C 3-10 carbocyclyl; wherein X − is a counterion.

2. The composition of claim 1 , wherein X is O.

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

4. The composition of claim 1 , wherein each instance of R 2 is independently hydrogen or a group of the formula (i), (ii), or (iii).

5. The composition of claim 1 , wherein the group of formula (iv) is of formula:

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

6. The composition 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:

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

8. The composition of claim 1 , wherein the compound is selected from the group consisting of:

and salts thereof.

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

and salts thereof.

10. The composition of claim 9 , wherein the compound is:

or salt thereof.

11. The composition of claim 1 , wherein the composition is a pharmaceutical composition.

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

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

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

15. The composition of claim 1 , wherein the polynucleotide is RNA.

16. The composition of claim 15 , wherein the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.

17. The composition of claim 15 , wherein the RNA is able to interfere with the expression of a specific gene in the biological cell.

18. The composition of claim 1 , wherein the polynucleotide is DNA.

19. The composition of claim 1 , wherein the polynucleotide encodes a protein or peptide.

20. The composition of claim 1 , wherein the composition is

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

• C07D241/08

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K39/12

  Viral antigens · CPC title