Fusogenic compounds for delivery of biologically active molecules

1. A fusogenic compound having Formula I

wherein each AA is independently an amino acid selected from the following structures, and any stereoisomer thereof:

wherein the amino acid is attached to an amphiphile at each of its amino groups and is attached to the linker at its C terminus;

wherein linker has the structure

—NH CH 2 n OCH 2 CH 2 m CH 2 p NH—

or

wherein Q 2 is

wherein Q 3 is

wherein X is —O—, —S—, or —NH—;

wherein n, p, q and t are independently for each occurrence 1 to 3;

wherein m is independently 1 to 10;

wherein r and s are independently for each occurrence 1 to 5; and

wherein each amphiphile is independently selected from Formula (II), Formula (IV), Formula (V), and Formula (VI), as follows:

wherein R 1 in Formula (II) is CH 2 (CH 2 ) n O(C═O)R 4 , CH 2 (CH 2 ) n NH(C═O)R 4 , CH 2 (CH 2 ) n (C═O)OR 4 , or CH 2 (CH 2 ) n (C═O)NHR 4 ;

wherein R 2 in Formula (II) is CH 2 (CH 2 ) m O(C═O)R 5 , CH 2 (CH 2 ) m NH(C═O)R 5 , CH 2 (CH 2 ) m (C═O)OR 5 , or CH 2 (CH 2 ) m (C═O)NHR 5 ;

wherein n and m in Formula (II) are each independently from 1 to 2; and R 4 and R 5 are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group; and

wherein R 3 in Formula (II) is branched or unbranched C(1-8) alkandiyl;

wherein R 1 in Formula (IV) is (C═O)R 4 ;

wherein R 2 in Formula (IV) is (C═O)OR 5 ;

wherein R 4 and R 5 in Formula (IV) are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group;

wherein Z in Formula (IV) is NH;

wherein p in Formula (IV) is 1 to 4;

wherein R 3 in Formula (IV) is

—C(1-12) alkyl group that is substituted with a —(C═O)— which is attached to AA;

wherein R 1 in Formula (V) is (C═O)OR 4 ;

wherein R 2 in Formula (V) is NH(C═O)R 5 ;

wherein R 4 and R 5 in Formula (V) are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group;

wherein R 3 in Formula (V) is branched or unbranched —O(C═O)—C(1-8)alkandiyl-(C═O)— which is attached to AA;

wherein R 1 in Formula (VI) is O(C═O)R 4 ;

wherein R 2 in Formula (VI) is O(C═O)R 5 ;

wherein R 4 and R 5 in Formula (VI) are independently for each occurrence a C(12-20) alkyl group, or a C(12-20) alkenyl group;

wherein R 3 in formula (VI) is

which is attached to AA

wherein one or two of the amphiphiles may optionally be absent and replaced by a pharmaceutically acceptable organic chemical group selected from an alkyl group, alkenyl, alkynyl, acetyl, Boc, Fmoc, TFA, and CBZ, having 1-400 atoms selected from carbon, oxygen, nitrogen, sulfur, fluorine, and hydrogen.

2. The fusogenic compound of claim 1 , wherein one or two of the amphiphiles are absent and replaced by the pharmaceutically acceptable organic chemical group.

3. The fusogenic compound of claim 2 , wherein the pharmaceutically acceptable organic chemical group is alkyl, alkenyl, alkynyl, acetyl, Boc, Fmoc, TFA, or CBZ.

4. The fusogenic compound of claim 2 , wherein the compound is selected from the following:

5. The fusogenic compound of claim 1 , wherein R 3 in Formula (II) is

branched or unbranched C(2-8)alkandiyl.

6. The fusogenic compound of claim 1 , wherein the compound is selected from the following:

7. The fusogenic compound of claim 1 , wherein R 4 and R 5 in Formula (IV) are independently for each occurrence a C(14-18) alkyl group, or a C(14-18) alkenyl group.

8. The fusogenic compound of claim 1 , wherein the compound is compound T10:

9. The fusogenic compound of claim 1 , wherein R 4 and R 5 in Formula (V) are independently for each occurrence a C(14-18) alkyl group, or a C(14-18) alkenyl group.

10. The fusogenic compound of claim 1 , wherein the compound is compound T12:

11. The fusogenic compound of claim 1 , wherein R 4 and R 5 in Formula (VI) are independently for each occurrence a C(14-18) alkyl group, or a C(14-18) alkenyl group.

12. The fusogenic compound of claim 1 , wherein the compound is compound T11

13. A composition comprising a fusogenic compound of claim 1 and a pharmaceutically acceptable carrier.

14. The composition of claim 13 , wherein the composition comprises nanoparticles or liposomes.

15. A pharmaceutical composition comprising a fusogenic compound of claim 1 , an active agent, and a pharmaceutically acceptable carrier.

16. The composition of claim 15 , wherein the fusogenic compound is from 0.01 mol % to 20 mol % of the lipids of the composition.

17. The composition of claim 15 , wherein the composition comprises nanoparticles or liposomes.

18. The composition of claim 15 , wherein the active agent is one or more nucleic acids.

19. The composition of claim 15 , wherein the active agent is one or more DNAs, RNAs, mRNAs, siRNAs, or microRNAs.

20. The composition of claim 15 , wherein the active agent is one or more RNA molecules.

21. The composition of claim 15 , wherein the active agent is selected from one or more RNAi molecules, one or more mRNA molecules, and modified forms thereof.

22. A composition comprising an active agent, a fusogenic compound of claim 1 , an ionizable lipid, a structural lipid, a stabilizer lipid, and a lipid for reducing immunogenicity of the composition.

23. The composition of claim 22 , wherein the active agent is one or more nucleic acids.