Protease inhibitor peptides
AssigneeScios Nova Inc.
InventorsR. TYLER WHITE, DEBORAH DAMM, DAVID D. LESIKAR, KATHLEEN MCFADDEN, BRETT L. GARRICK
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Abstract
Analogues of the Kunitz Protease Inhibitor (KPI) domain of amyloid precursor protein bind to and inhibit activity of serine proteases, including kallikrein, plasmin and coagulation factors such as factors VIIa, IXa, Xa, XIa, and XIIa. Pharmaceutical compositions containing the KPI analogues, along with methods for using such compositions, are useful for ameliorating and treating clinical conditions associated with increased serine protease activity, such as blood loss related to cardiopulmonary bypass surgery. Nucleic acid sequences encoding these analogues and systems for expression of the peptides of the invention are provided.
Claims79
A protease inhibitor comprising the sequence:
- X1-Val-Cys-Ser-Glu-Gln-Ala-Glu-X2-Gly-X3-Cys-Arg-Ala-X4-X5-X6-X7-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-X8-Tyr-Gly-Gly-Cys-X9-X10-X11-X12-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,
- wherein:
- X1 is selected from Glu-Val-Val-Arg-Glu-, Asp, or Glu;
- X2 is selected from Thr, Val, Ile and Ser;
- X3 is selected from Pro and Ala;
- X4 is selected from Arg, Ala, Leu, Gly, or Met;
- X5 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X6 is selected from-Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X7 is selected from Arg, His, or Ala;
- X8 is selected from Phe, Val, Leu, or Gly;
- X9 is selected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr;
- X10 is selected from Ala, Arg, or Gly;
- X11 is selected from Lys, Ala, or Asn;
- X12 is selected from Ser, Ala, or Arg;
- provided that:
- when X4 is Arg, X6 is Ile;
- when X9 is Arg, X4 is Ala or Leu;
- when X9 is Tyr, X4 is Ala or X5 is His;
- and
- either X5 is not Ile;
- or X6 is not Ser;
- or X9 is not Leu, Phe, Met, Tyr, or Asn;
- or X10 is not Gly;
- or X11 is not Asn;
- or X12 is not Arg.
A protease inhibitor comprising the sequence:
- X1-Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X2-X3-X4-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X5-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,
- wherein:
- X1 is selected from Glu-Val-Val-Arg-Glu-, Asp, or Glu;
- X2 is selected from Ala, Leu, Gly, or Met;
- X3 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X4 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X5 is selected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr;
- provided that:
- when X5 is Arg, X2 is Ala or Leu;
- when X5 is Tyr, X2 is Ala or X3 is His;
- and
- either X3 is not Ile;
- or X4 is not Ser;
- or X5 is not Leu, Phe, Met, Tyr, or Asn.
A protease inhibitor comprising the sequence:
- Glu-Val-Val-Arg-Glu-Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X1-X2-X3-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X4-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile, wherein:
- X1 is selected from Ala, Leu, Gly, or Met;
- X2 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X3 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X4 is selected from Gly, Arg, Leu, Met, or Tyr;
- provided that:
- when X1 is Ala, X2 is Ile, His, or Leu;
- when X1 is Leu, X2 is Ile or His;
- when X1 is Leu and X2 is Ile, X3 is not Ser;
- when X1 is Gly, X2 is Ile;
- when X4 is Arg, X1 is Ala or Leu;
- when X4 is Tyr, X1 is Ala or X2 is His;
- and
- either X1 is not Met, or X2 is not Ile, or X3 is not Ser, or X4 is not Gly.
A protease inhibitor comprising the sequence:
- X1-Val-Cys-Ser-Glu-Gln-Ala-Glu-X2-Gly-Pro-Cys-Arg-Ala-X3-X4-X5-X6-Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X7-Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,
- wherein:
- X1 is selected from Glu-Val-Val-Arg-Glu-, Asp, or Glu;
- X2 is selected from Thr, Val, Ile and Ser;
- X3 is selected from Arg, Ala, Leu, Gly, or Met;
- X4 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X5 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X6 is selected from Arg, His, or Ala;
- and
- X7 is selected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr.
Dependencies are inferred from the claim text.