Linear Natriuretic Peptide Constructs

Abstract

Linear constructs with an N-terminus and a C-terminus which bind to a natriuretic peptide receptor and include a plurality of amino acid residues and at least one amino acid surrogate of formula I:

Description

Claims

1. A linear peptide construct with an N-terminus and a C-terminus which binds to a natriuretic peptide receptor and comprises a plurality of amino acid residues and at least one amino acid surrogate of formula I:

2. The construct of claim 1, further comprising at least one prosthetic group covalently bonded to a reactive group in a side chain or terminal group of at least one of the amino acid residues, to an amine group or reactive group in an amine capping group where the surrogate is at the N-terminus position of the construct, or to a carboxyl group, amine group or reactive group in a C-terminus capping group where the surrogate is at the C-terminus position of the construct.

3. The construct of claim 1, wherein the surrogate is at the C-terminus position of the construct and J is a C-terminus capping group consisting of: —(CH2)m—OH,—C(═O)—(CH2)m—N(v1)(v2),—C(═O)—O—(CH2)m—CH3,—O—(CH2)m—CH3,—O—(CH2)m—N(v1)(v2),—O—(CH2)m—OH,—C(═O)—NH—(CH2)m—CH3,—C(═O)—NH—(CH2)m—N(v1)(v2),—C(═O)—N—((CH2)m—N(v1)(v2))2,—C(═O)—NH—CH(—C(═O)—OH)—(CH2)m—N(v1)(v2),—C(═O)—NH—(CH2)m—NH—C(═O)—CH(N(v1)(v2))((CH2)m—N(v1)(v2)), or—C(═O)—NH—CH(—C(═O)—N(v1)(v2))-(CH2)m—N(v1)(v2);

4. The construct of claim 1, wherein the surrogate is at the C-terminus position of the construct and J is a C-terminus capping group consisting of an omega amino aliphatic, terminal aryl or aralkyl group or any single natural or unnatural α-amino acid, β-amino acid, α,α-disubstituted amino acid, N-substituted amino acid, including all (R) or (S) configurations of the foregoing, optionally in combination with a C-terminus capping group as defined in claim 2.

5. The construct of claim 1, wherein the surrogate is at the N-terminus position of the construct and Q is an amine capping group consisting of —(CH2)m—N(v3)(v4),—(CH2)m—CH3,—(CH2)m—O(v3),—(CH2)m—C(═O)-(v3),—(CH2)m—C(═O)—O-(v3),—(CH2)m—S(v3),—C(═O)—(CH2)m—CH3,—C(═O)—(CH2)m—N(v3)(v4),—C(═O)—(CH2)m—C(═O)-(v3),—C(═O)—(CH2)m—O(v3), or—C(═O)—(CH2)m—S(v3);where v3 and v4 are each independently H, a C1 to C17 linear or branched alkyl chain or a C2 to C19 linear or branched alkyl acyl chain, on the proviso that if one of v3 or v4 is an alkyl acyl chain, then the other of v3 or v4 is H, and m is 0 to 17.

6. The construct of claim 1, wherein the construct comprises at least one surrogate of formula II:

7. The construct of claim 1, wherein at least one surrogate of formula I is at the C-terminus of the construct and is covalently bonded thereto by a peptide bond, such that the surrogate has the formula:

8. The construct of claim 1 wherein at least one surrogate of formula I is at the N-terminus of the construct and is covalently bonded thereto by one peptide bond, such that the surrogate has the formula:

9. The construct of claim 1, wherein at least one surrogate of formula I is at the C-terminus of the construct, Q is a bond, and R and R′ thereof are each independently H or a natural or unnatural amino acid side chain moiety or derivative of an amino acid side chain moiety with a heteroatom group comprising at least one nitrogen atom, on the provisio that at least one of R and R′ is not H.

10. The construct of claim 9, wherein at least one of R and R′ with a heteroatom group comprising at least one nitrogen atom is of the formula —(CH2)y—R′ where y is 1 to 5 and R″ is a heteroatom group comprising at least one nitrogen atom.

11. The construct of claim 10, wherein R″ is:

12. The construct of claim 1, wherein the natriuretic peptide receptor is a receptor for ANP, BNP, CNP, sCP, DNP, TNP-a, TNP-b or TNP-c.

13. The construct of claim 1, wherein the plurality of amino acid residues comprise natural or unnatural α-amino acid, β-amino acid, α,α-disubstituted amino acid, N-substituted amino acid, including all (R) or (S) configurations of α,α-disubstituted amino acids where the substituents are different, or a combination of the foregoing.

14. The construct of claim 1, wherein at least two of the plurality of amino acid residues are joined by a non-peptide bond.

15. The construct of claim 14, wherein the at least one non-peptide bond is —CH2—NH—, —CH2—S—, —CH2—O—, or —C(═O)—CH2—, an isostere of any of the foregoing, or —CH2—CH2— or —CH═CH—.

16. The construct of claim 1, comprising from twelve to fifteen amino acid residues and one surrogate of formula I.

17. The construct of claim 1, comprising from eleven to fourteen amino acid residues and two surrogates of formula I.

18. The construct of claim 1, comprising from eleven to fourteen amino acid residues, one surrogate of formula II and one surrogate of formula I at either the N-terminus or the C-terminus.

19. The construct of claim 1, wherein for at least one surrogate one of R and R′ is H, x is 1, Y is C═O, W is NH, Z is H and n is 0.

20. The construct of claim 3, wherein the surrogate is at the C-terminus position of the construct and J is —C(═O)—NH2, —C(═O)—OH, —CH2—OH, —C(═O)—(CH2)4—NH2, —C(═O)—(CH2)5—NH2, —C(═O)—(CH2)6—NH2, —C(═O)—(CH2)7—NH2, or —C(═O)—(CH2)8—NH2.

21. The construct of claim 2, wherein the prosthetic group comprises at least one polymeric sequence comprising repeat units including carbon and hydrogen atoms.

22. The construct of claim 21, wherein the repeat units further comprise additional atoms.

23. The construct of claim 21, wherein the repeat units further comprise oxygen atoms.

24. The construct of claim 21, wherein the polymeric sequence is a water-soluble polymer sequence.

25. The construct of claim 21, wherein the polymeric sequence is poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline or poly(acryloylmorpholine).

26. The construct of claim 25, wherein the poly(alkylene oxide) is poly(ethylene glycol) (PEG).

27. The construct of claim 26, wherein the prosthetic group comprising PEG is derivatized with a linking group.

28. The construct of claim 26, wherein the PEG has a molecular weight range of about 200 MW to about 40,000 MW.

29. The construct of claim 2, wherein the prosthetic group comprises an amine reactive group.

30. The construct of claim 29, wherein the prosthetic group is covalently bonded to a reactive amine in a side chain of at least one of the amino acid residues.

31. The construct of claim 29, wherein the prosthetic group is covalently bonded to a reactive amine in a C-terminus capping group where the surrogate is at the C-terminus position of the construct.

32. The construct of claim 29, wherein the prosthetic group is covalently bonded to a reactive amine in an amine capping group where the surrogate is at the N-terminus position of the construct.

33. The construct of claim 29, wherein the prosthetic group is covalently bonded to a reactive amine in an amine group of the surrogate where the surrogate is at the N-terminus position of the construct.

34. The construct of claim 2, wherein the prosthetic group comprises a carboxyl reactive group.

35. The construct of claim 34, wherein the prosthetic group is covalently bonded to a reactive carboxyl in a side chain of at least one of the amino acid residues.

36. The construct of claim 34, wherein the prosthetic group is covalently bonded to a reactive carboxyl in a C-terminus capping group where the surrogate is at the C-terminus position of the construct.

37. The construct of claim 2, wherein the prosthetic group comprises a thiol reactive group.

38. The construct of claim 37, wherein the prosthetic group is covalently bonded to a reactive thiol in a side chain of at least one of the amino acid residues.

39. The construct of claim 37, wherein the prosthetic group is covalently bonded to a reactive thiol in an amine capping group where the surrogate is at the N-terminus position of the construct.

40. A linear peptide construct comprising from eleven to thirteen amino acid residues and at least one amino acid surrogate at any position other than the C-terminus position of the following formula:

41. A linear peptide construct of formula III: Aaa1-Aaa2-Aaa3-Aaa4-Aaa5-Aaa6-Aaa7-Aaa8-Aaa9-Aaa10-Aaa11-Aaa12-Aaa13-Aaa14-Aaa15 (III)wherein: Aaa1 is an L- or D-isomer of an α-amino acid or β-amino acid including or derived from Nle, Ala, Leu, Ile, Val, Arg, Phe, Lys, Tyr, Asp, Nva, Met, Met(O), or Met(O2), or an α,α-disubstituted amino acid derived from Nle, Ala, Leu, Ile, Val, Arg, Phe, Lys, Tyr, Asp, Val, Nva, Met, Met(O), or Met(O2), including all (R) or (S) configurations of α,α-disubstituted amino acids where the substituents are different, or Aaa1 is an acyl wherein the organic group is a C2 to C18 linear alkyl, a C3 to C17 branched alkyl, a C2 to C18 linear alkenyl or alkynyl or a C3 to C18 branched alkenyl or alkynyl, or Aaa1 is an amino acid surrogate of the structure:

42. The construct of claim 41, where one of Aaa1 through Aaa15 is an amino acid surrogate.

43. The construct of claim 41, where two of Aaa1 through Aaa15 are an amino acid surrogate.

44. The construct of claim 41, where three or more of Aaa1 through Aaa15 are an amino acid surrogate.

45. The construct of claim 41, wherein at least one of Aaa3, Aaa5, Aaa6, Aaa7, Aaa9, Aaa10, or Aaa12 is an L- or D-isomer of Ala.

46. The construct of claim 41, further comprising at least one prosthetic group covalently bonded to a reactive group in a side chain or terminal group of at least one of the amino acid residues, to an amine group or reactive group in an amine capping group where the surrogate is at the N-terminus position of the construct, or to a carboxyl group, amine group or reactive group in a C-terminus capping group where the surrogate is at the C-terminus position of the construct.

47. A linear peptide construct of formula IV:

48. A linear peptide construct of formula V:

49. A linear peptide construct of formula VI:

50. A linear peptide construct of formula VII or VIII:

51. A linear peptide construct of formula IX or X:

52. A linear peptide construct of formula XI or XII:

53. A linear peptide construct of formula V.