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

1. A method of treating a liver disease from which a subject suffers, comprising administering to the subject in need thereof an effective amount of a composition comprising a polynucleotide and a compound of Formula (III):

or a 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, 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 each instance of R 1 is a group of formula (iv).

3. 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:

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

and salts thereof.

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

and salts thereof.

6. The method of claim 5 , wherein the compound is:

or salt thereof.

7. The method of claim 1 , wherein X is NR X , wherein R X is hydrogen or a nitrogen protecting group.

8. The method of claim 1 , wherein X is 0.

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

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

11. The method of claim 10 , wherein the RNA carries out RNA interference.

12. The method of claim 10 , wherein the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.

13. The method of claim 10 , wherein upon administration of the composition to the subject, the RNA is able to interfere with the expression of a specific gene in a biological cell.

14. The method of claim 1 , wherein the polynucleotide is DNA.

15. The method of claim 1 , wherein the polynucleotide encodes a protein or peptide.

16. The method of claim 1 , wherein the liver disease is selected from the group consisting of drug-induced liver injury, hepatitis, non-alcoholic fatty liver disease, alcohol-induced liver disease, hypercholesterolemia, transthyretin-related hereditary amyloidosis, liver cirrhosis, liver cancer, primary biliary cirrhosis, cholestasis, cystic disease of the liver, and primary sclerosing cholangitis.