Tertiary amino lipidated cationic peptides for nucleic acid delivery
The present disclosure relates to tertiary amino lipidated and/or PEGylated cationic peptide compounds and complexes thereof with nucleic acids for endocellular delivery, methods for preparing the compounds and complexes, and methods for delivering polyanionic compounds to cells.
1. A tertiary amino lipidated and/or PEGylated cationic peptide compound of formula (I) or a salt thereof:
wherein:
s is an integer from 1 to 5;
R 1 is —H
each R 3 is independently selected from C 8 -C 24 alkyl;
R 5 is selected from hydroxyalkyl, hydroxyether, and hydroxylheteroalkyl;
R 7 is —H, alkyl, acyl, —OH, —OR 7a , —NH 2 , -NHR 7a , or a lipid moiety, wherein
R 7a is alkyl, acyl, or a lipid moiety; and
each R a and R b are independently —H, C 1 -C 4 -alkyl, or a side chain moiety found on a naturally- or non-naturally-occurring amino acid.
2. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein s is 3 or 4.
3. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein each R 3 is independently C 8 -C 12 alkyl.
4. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein each R 3 is independently selected from the group consisting of
5. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein each R 3 is independently selected from the group consisting of
6. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein R a and R b are —H.
7. A complex comprising one or more of the tertiary amino lipidated and/or PEGylated cationic peptide compounds of claim 1 , complexed to a polyanionic compound.
8. The complex of claim 7 , wherein the polyanionic compound comprises a nucleic acid.
9. The complex of claim 7 , wherein the polyanionic compound comprises an mRNA encoding a polypeptide.
10. The complex of claim 7 , wherein the polyanionic compound comprises a nucleic acid and wherein the one or more tertiary amino lipidated and/or PEGylated cationic peptide compounds and the nucleic acid are present in the complex at a mass ratio between 0.5:1 and 50:1.
11. The complex of claim 7 , wherein the complex comprises: the one or more tertiary amino lipidated and/or PEGylated cationic peptide compounds, a nucleic acid, a phospholipid, a structural lipid, and a PEG lipid.
12. A method of delivering a polyanionic compound to a cell comprising contacting the cell with the complex of claim 7 .
13. The method of claim 12 , wherein the polyanionic compound comprises an mRNA encoding a polypeptide and the cell expresses the polypeptide after being contacted with the complex.
14. A method of forming the complex of claim 7 , comprising contacting the one or more tertiary amino lipidated and/or PEGylated cationic peptide compounds with the polyanionic compound.
15. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein R 7 is NH 2 .
16. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein s is 4 and:
two R 3 are
and two R 3 are
or
each R 3 is
17. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein R 5 is hydroxyalkyl or hydroxyether.
18. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 17 , wherein R 5 is hydroxyalkyl.
19. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 18 , wherein R 5 is
20. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein s is 4; each R 3 independently is
R 5 is hydroxyalkyl; R 7 is NH 2 ; and each R a and R b independently is H.
21. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 20 , wherein each R 3 independently is
22. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein the compound of formula (I) is
23. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 5 , wherein each R 3 is
24. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 17 wherein R 5 is
25. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 23 , wherein R 5 is
26. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 1 , wherein s is 4; each R 3 independently is
R 5 is
R 7 is NH 2 ; and each R a and R b is H.
27. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 25 , wherein each R 3 is
28. The tertiary amino lipidated and/or PEGylated cationic peptide compound of claim 25 , wherein R 5 is