Protease inhibitor peptides
AssigneeScios, Inc.
InventorsR. Tyler White, Deborah Damm, David D. Lesikar, Kathleen McFadden, Brett L. Garrick
Life of this patent
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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.
Claims32
An isolated DNA molecule comprising a DNA sequence encoding a kallikrein inhibitor comprising the sequence(SEQ ID NO:1):
- X.sup.1 -Val-Cys-Ser-Glu-Gln-Ala-Glu-X.sup.2 -Gly-X.sup.3 -Cys-Arg-Ala-X.sup.4 -X.sup.5 -X.sup.6 -X.sup.7 -Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-X.sup.8 -Tyr-Gly-Gly-Cys-X.sup.9 -X.sup.10 -X.sup.11 -X.sup.12 -Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-Ala-Ile,
- wherein:
- X.sup.1 is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, or Glu;
- X.sup.2 is selected from Thr, Val, Ile and Ser;
- X.sup.3 is selected from Pro and Ala;
- X.sup.4 is selected from Arg, Ala, Leu, Gly, or Met;
- X.sup.5 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X.sup.6 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X.sup.7 is selected from Arg, His, or Ala;
- X.sup.8 is selected from Phe, Val, Leu, or Gly;
- X.sup.9 is selected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr;
- X.sup.10 is selected from Ala, Arg, or Gly;
- X.sup.11 is selected from Lys, Ala, or Asn;
- X.sup.12 is selected from Ser, Ala, or Arg;
- provided that:
- when X.sup.4 is Arg, X.sup.6 is Ile;
- when X.sup.9 is Arg, X.sup.4 is Ala or Leu;
- when X.sup.9 is Tyr, X.sup.4 is Ala or X.sup.5 is His;
- and
- either X.sup.5 is not Ile;
- or X.sup.6 is not Ser;
- or X.sup.9 is not Gly, Leu, Phe, Met, Tyr, or Asn;
- or X.sup.10 is not Gly;
- or X.sup.11 is not Asn;
- or X.sup.12 is not Arg.
An isolated DNA molecule comprising a sequence encoding a kallikrein inhibitor comprising the sequence(SEQ ID NO:2):
- X.sup.1 -Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X.sup.2 -X.sup.3 -X.sup.4 -Arg-Trp-Tyr-Phe -Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-Cys-X.sup.5 -Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-A la-Ile,
- wherein:
- X.sup.1 is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, or Glu;
- X.sup.2 is selected from Ala, Leu, Gly, or Met;
- X.sup.3 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X.sup.4 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X.sup.5 is selected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr;
- provided that:
- when X.sup.5 is Arg, X.sup.2 is Ala or Leu;
- when X.sup.5 is Tyr, X.sup.2 is Ala or X.sup.3 is His;
- and
- either X.sup.3 is not Ile;
- or X.sup.4 is not Ser;
- or X.sup.5 is not Gly, Leu, Phe, Met, Tyr, or Asn.
An isolated DNA molecule comprising a DNA sequence encoding a kallikrein inhibitor comprising the sequence(SEQ ID NO:4):
- Glu-Val-Val-Arg-Glu-Val-Cys-Ser-Glu-Gln-Ala-Glu-Thr-Gly-Pro-Cys-Arg-Ala-X.s up.1 -X.sup.2 -X.sup.3 -Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-C ys-X.sup.4 -Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-A la-Ile,
- wherein:
- X.sup.1 is selected from Ala, Leu, Gly, or Met;
- X.sup.2 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X.sup.3 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X.sup.4 is selected from Gly, Arg, Leu, Met, or Tyr;
- provided that:
- when X.sup.1 is Ala, X.sup.2 is Ile, His, or Leu;
- when X.sup.1 is Leu, X.sup.2 is Ile or His;
- when X.sup.1 is Leu and X.sup.2 is Ile, X.sup.3 is not Ser;
- when X.sup.1 is Gly, X.sup.2 is Ile;
- when X.sup.4 is Arg, X.sup.1 is Ala or Leu;
- when X.sup.4 is Tyr, X.sup.1 is Ala or X.sup.2 is His;
- and
- either X.sup.1 is not Met, or X.sup.2 is not Ile, or X.sup.3 is not Ser, or X.sup.4 is not Gly.
An isolated DNA molecule comprising a DNA sequence encoding a kallikrein inhibitor comprising the sequence(SEQ ID NO:5):
- X.sup.1 -Val-Cys-Ser-Glu-Gln-Ala-Glu-X.sup.2 -Gly-Pro-Cys-Arg-Ala-X.sup.3 -X.sup.4 -X.sup.5 -X.sup.6 -Arg-Trp-Tyr-Phe-Asp-Val-Thr-Glu-Gly-Lys-Cys-Ala-Pro-Phe-Phe-Tyr-Gly-Gly-C ys-X.sup.7 -Gly-Asn-Arg-Asn-Asn-Phe-Asp-Thr-Glu-Glu-Tyr-Cys-Met-Ala-Val-Cys-Gly-Ser-A la-Ile,
- wherein:
- X.sup.1 is selected from Glu-Val-Val-Arg-Glu-(SEQ ID NO:2), Asp, or Glu;
- X.sup.2 is selected from Thr, Val, Ile and Ser;
- X.sup.3 is selected from Arg, Ala, Leu, Gly, or Met;
- X.sup.4 is selected from Ile, His, Leu, Lys, Ala, or Phe;
- X.sup.5 is selected from Ser, Ile, Pro, Phe, Tyr, Trp, Asn, Leu, His, Lys, or Glu;
- X.sup.6 is selected from Arg, His, or Ala;
- and
- X.sup.7 is selected from Gly, Ala, Lys, Pro, Arg, Leu, Met, or Tyr, and either X.sup.4 is not Ile;
- or X.sup.5 is not Ser;
- or X.sup.7 is not Gly, Leu, Phe, Met, Tyr, or Asn.
Dependencies are inferred from the claim text.