Therapeutic peptides
The present invention provides a peptide, peptidomimetic or amino acid derivative having a net positive charge of at least +2 and incorporating a disubstituted β amino acid, each of the substituting groups in the β amino acid, which may be the same or different, comprises at least (7) non-hydrogen atoms, is lipophilic and has at least one cyclic group, one or more cyclic groups within a substituting group may be linked or fused to one or more cyclic groups within the other substituting group and where cyclic groups are fused in this way the combined total number of non-hydrogen atoms for the two substituting groups is at least (12), for use as a cytolytic therapeutic agent; as well as non therapeutic uses of these molecules and certain defined novel compounds from within this definition.
1. A method of treating a bacterial infection, which method comprises administering to a subject in need of such treatment a peptide, peptidomimetic or amino acid derivative having a net positive charge of at least +2 and incorporating a group of formula I:
wherein any 2 from R 1 , R 2 , R 3 and R 4 are hydrogen atoms and 2 are substituting groups, which may be the same or different, comprise at least 7 non-hydrogen atoms, are lipophilic and include a cyclic group, said cyclic group not being attached directly either to the α or β carbon atom and optionally being linked or fused to a cyclic group in the other substituting group, where cyclic groups are fused the combined total number of non-hydrogen atoms for the two substituting groups is at least 12, and wherein X represents O, C, N or S, and wherein said peptide, peptidomimetic or amino acid derivative is 1 to 4 amino acids or equivalent subunits in length.
2. The method as claimed in claim 1 wherein the two substituting groups are the same.
3. The method as claimed in claim 1 wherein the group of formula I is a β 2,2 or β 3,3 distributed amino acid.
4. The method as claimed in claim 1 wherein each of the lipophilic substituting groups comprises an optionally substituted phenyl or cyclohexyl group.
5. The method as claimed in claim 4 wherein said phenyl or cyclohexyl groups are separated from the α or β carbon atom of the group of formula I by 1 to 4 linking atoms.
6. The method as claimed in claim 1 wherein each of the lipophilic substituting groups comprises 8 to 12 non-hydrogen atoms.
7. The method as claimed in claim 1 wherein the C terminus of the peptide, peptidomimetic or amino acid derivative is amidated and optionally substituted.
8. The method as claimed in claim 1 wherein the peptide or peptidomimetic incorporates a cationic amino acid.
9. The method as claimed in claim 8 wherein the cationic amino acid is arginine or lysine.
10. A method of treating tumour cells comprising administering to a subject in need of such treatment a peptide, peptidomimetic or amino acid derivative having a net positive charge of at least +2 and incorporating a group of formula I:
wherein any 2 from R 1 , R 2 , R 3 and R 4 are hydrogen atoms and 2 are substituting groups, which may be the same or different, comprise at least 7 non-hydrogen atoms, are lipophilic and include a cyclic group, said cyclic group not being attached directly either to the α or β carbon atom and optionally being linked or fused to a cyclic group in the other substituting group, where cyclic groups are fused the combined total number of non-hydrogen atoms for the two substituting groups is at least 12, and wherein X represents O, C, N or S, and wherein said peptide, peptidomimetic or amino acid derivative is 1 to 4 amino acids or equivalent subunits in length, wherein the tumour cell is selected from the group consisting of prostate carcinoma, ovarian adenocarcinoma, breast carcinoma, melanoma, squamous oral carcinoma, and colorectal adenocarcinoma.
11. The method as claimed in claim 10 wherein the two substituting groups are the same.
12. The method as claimed in claim 10 wherein the group of formula I is a β 2,2 or β 3,3 disubstituted amino acid.
13. The method as claimed in claim 10 wherein each of the lipophilic substituting groups comprises an optionally substituted phenyl or cyclohexyl group.
14. The method as claimed in claim 13 wherein said phenyl or cyclohexyl groups are separated from the α or β carbon atom of the group of formula I by 1 to 4 linking atoms.
15. The method as claimed in claim 10 wherein each of the lipophilic substituting groups comprises 5 to 12 non-hydrogen atoms.
16. The method as claimed in claim 10 wherein the C terminus of the peptide, peptidomimetic or amino acid derivative is amidated and optionally substituted.
17. The method as claimed in claim 10 wherein the peptide or peptidomimetic incorporates a cationic amino acid.
18. The method as claimed in claim 17 wherein the cationic amino acid is arginine or lysine.
19. An ex vivo method of bacterial cell lysis comprising contacting said bacterial cells with a peptide, peptidomimetic or amino acid derivative having a net positive charge of at least +2 and incorporating a group of formula I:
wherein any 2 from R 1 , R 2 , R 3 and R 4 are hydrogen atoms and 2 are substituting groups, which may be the same or different, comprise at least 7 non-hydrogen atoms, are lipophilic and include a cyclic group, said cyclic group not being attached directly either to the α or β carbon atom and optionally being linked or fused to a cyclic group in the other substituting group, where cyclic groups are fused the combined total number of non-hydrogen atoms for the two substituting groups is at least 12, and wherein X represents O, C, N or S, and wherein said peptide, peptidomimetic or amino acid derivative is 1 to 4 amino acids or equivalent subunits in length.
20. The method as claimed in claim 19 wherein the two substituting groups are the same.
21. The method as claimed in claim 19 wherein the group of formula I is a β 2,2 or β 3,3 disubstituted amino acid.
22. The method as claimed in claim 19 wherein each of the lipophilic substituting groups comprises an optionally substituted phenyl or cyclohexyl group.
23. The method as claimed in claim 19 wherein said phenyl or cyclohexyl groups are separated from the α or β carbon atom of the group of formula I by 1 to 4 linking atoms.
24. The method as claimed in claim 19 wherein each of the lipophilic substituting groups comprises 8 to 12 non-hydrogen atoms.
25. The method as claimed in claim 19 wherein the C terminus of the peptide, peptidomimetic or amino acid derivative is amidated and optionally substituted.
26. The method as claimed in claim 19 wherein the peptide or peptidomimetic incorporates a cationic amino acid.
27. The method as claimed in claim 26 wherein the cationic amino acid is arginine or lysine.
28. A peptide, peptidomimetic or amino acid derivative having a net positive charge of at least +2 which incorporates a group of formula I:
wherein any 2 from R 1 , R 2 , R 3 and R 4 are hydrogen atoms and 2 are substituting groups, which may be the same or different, comprise at least 7 non-hydrogen atoms, are lipophilic and include a cyclic group, said cyclic group not being attached directly either to the α or β carbon atom and optionally being linked or fused to a cyclic group in the other substituting group, where cyclic groups are fused the combined total number of non-hydrogen atoms for the two substituting groups is at least 12, and wherein X represents O, C, N or S, and wherein said peptide, peptidomimetic or amino acid derivative is 1 to 4 amino acids or equivalent subunits in length.
29. A formulation comprising the peptide, peptidomimetic or amino acid derivative as claimed in claim 28 and a diluent, carrier or excipient.
30. The peptide, peptidomimetic or amino acid derivative as claimed in claim 28 wherein the two substituting groups are the same.
31. The peptide, peptidomimetic or amino acid derivative as claimed in claim 28 wherein the group of formula I is a β 2,2 or β 3,3 disubstituted amino acid.
32. The peptide, peptidomimetic or amino acid derivative as claimed in claim 28 wherein each of the lipophilic substituting groups comprises an optionally substituted phenyl or cyclohexyl group.
33. The peptide, peptidomimetic or amino acid derivative as claimed in claim 32 wherein said phenyl of cyclohexyl groups are separated from the α or β carbon atom of the group of formula I by 1 to 4 linking atoms.
34. The peptide, peptidomimetic or amino acid derivative as claimed in claim 28 wherein each of the lipophilic substituting groups comprises 8 to 12 non-hydrogen atoms.
35. The peptide, peptidomimetic or amino acid derivative as claimed in claim 28 wherein the C terminus of the peptide, peptidomimetic or amino acid derivative is amidated and optionally substituted.
36. The peptide, peptidomimetic or amino acid derivative as claimed in claim 28 wherein the peptide or peptidomimetic incorporates a cationic amino acid.
37. The peptide, peptidomimetic or amino acid derivative as claimed in claim 36 wherein the cationic amino acid is arginine or lysine.