Cardiovascular Therapeutics
Compounds and compositions comprising a B-type natriuretic signal peptide fragment agent, and methods of use thereof, are provided for the treatment or prevention of cardiovascular diseases, disorders, and conditions.
1 . A pharmaceutical composition for use in preventing and/or treating a cardiovascular disorder, comprising a therapeutically effective amount of a Type-B natriuretic signal peptide fragment agent and a pharmaceutically acceptable carrier.
2 .- 10 . (canceled)
11 . A substantially pure peptide having the amino acid sequence selected from the group consisting of
LH X 1 X 2 X 3 X 4 X 5 X 6 X 7 X g a.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2 is Val, Leu or Ile or Gly; X 3 is Leu, Val, Ile, Ala, Tyr or Gly; X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 5 is Pro, Ala, Arg or Ser; X 6 is Pro, Ala, Arg or Ser; X 7 is Gln, Asn or Gly; and X 8 is Ser, Thr or Gly;
LH X 1 X 2 X 3 X 4 X 5 X 6 X 7 b.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2 is Val, Leu, Ile or Gly; X 3 is Leu, Val, Ile, Ala, Tyr or Gly; X 4 is; Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 5 is Pro, Ala, Arg or Ser; X 6 is Pro, Ala, Arg or Ser; and X 7 is Arg, Gln, Asn or Gly; provided that
where X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 2 is Val, Leu or Ile or Gly, X 1 can also be Leu, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 3 is Leu, Val, Ile, Ala, Tyr or Gly, X 1 can also be Leu, X 2 can also be Ala, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 5 is Pro, Ala, Arg or Ser, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 6 can also be Gly, and X 7 can also be Arg;
where X 6 is Pro, Ala, Arg or Ser, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, and X 7 can also be Arg;
where X 7 is Lys, Gln, Asn or Gly, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, and X 6 can also be Gly;
LH X 1 X 2 X 3 X 4 X 5 X 6 c.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2 is Val, Leu, Ile or Gly; X 3 is Leu, Val, Ile, Ala, Tyr or Gly; X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 5 is Pro, Ala, Arg or Ser; and X 6 is Pro, Ala, Arg or Ser; provided that
where X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 2 is Val, Leu or Ile or Gly, X 1 can also be Leu, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 3 is Leu, Val, Ile, Ala, Tyr or Gly, X 1 can also be Leu, X 2 can also be Ala, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 5 is Pro, Ala, Arg or Ser, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 6 can also be Gly, and X 7 can also be Arg;
where X 6 is Pro, Ala, Arg or Ser, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, and X 7 can also be Arg;
L H X 1 X 2 X 3 X 4 1 S X 5 d.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2 is Val, Leu, Ile or Gly; X 3 is Leu, Val, Ile, Ala, Tyr or Gly; X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; and X 5 is Pro, Ala, Arg or Ser; provided that
where X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 2 is Val, Leu or Ile or Gly, X 1 can also be Leu, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 3 is Leu, Val, Ile, Ala, Tyr or Gly, X 1 can also be Leu, X 2 can also be Ala, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 5 is Pro, Ala, Arg or Ser, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 6 can also be Gly, and X 7 can also be Arg;
L H X 1 X 2 X 3 X 4 e.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2 is Val, Leu, Ile or Gly; X 3 is Leu, Val, Ile, Ala, Tyr or Gly; and X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; provided that
where X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2 can also be Ala, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 2 is Val, Leu or Ile or Gly, X 1 can also be Leu, X 3 can also be Phe, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 3 is Leu, Val, Ile, Ala, Tyr or Gly, X 1 can also be Leu, X 2 can also be Ala, X 4 can also be Leu, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
where X 4 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 1 can also be Leu, X 2 can also be Ala, X 3 can also be Phe, X 5 can also be Gly, X 6 can also be Gly, and X 7 can also be Arg;
L H X 1 X 2 X 3 f.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; X 2 is Val, Leu, Ile or Gly; and X 3 is Leu, Val, Ile, Ala, Tyr or Gly; provided that
where X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2 can also be Ala, and X 3 can also be Phe;
where X 2 is Val, Leu or Ile or Gly, X 1 can also be Leu, and X 3 can also be Phe; and
where X 3 is Leu, Val, Ile, Ala, Tyr or Gly, X 1 can also be Leu, and X 2 can also be Ala;
L H X 1 X 2 g.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly; and X 2 is Val, Leu, Ile or Gly; provided that
where X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly, X 2 can also be Ala; and
where X 2 is Val, Leu or Ile or Gly, X 1 can also be Leu; and
L H X 1 h.
wherein X 1 is Norleucine, Ile, Val, Met, Ala, Phe or Gly.
12 . A method selected from the group consisting of:
a. treating a subject having or at risk for developing a cardiovascular disorder, comprising increasing Type-B natriuretic signal peptide fragment activity in said subject;
b. treating a subject having or at risk for developing an acute coronary syndrome, comprising administering to the subject a composition comprising a Type-B natriuretic signal peptide fragment or Type-B natriuretic signal peptide fragment analog; and
c. preparing a medicament for preventing or treating a cardiovascular disorder or an acute coronary syndrome, comprising bringing together a therapeutically effective amount of a Type-B natriuretic signal peptide fragment or a Type-B natriuretic signal peptide fragment analog and a pharmaceutically acceptable carrier;
wherein the Type-B natriuretic signal peptide fragment optionally comprises a substantially pure peptide according to claim 11 , or an analog, derivative, or prodrug or such a peptide.
13 .- 19 . (canceled)