Compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator
AssigneeThe Trustees of the University of Pennsylvania
InventorsDouglas Cines, Abd Al-Roof Higazi
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Abstract
The invention includes compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator.
Claims15
A method of inhibiting PAI-1 binding to scuPA and tcuPA in a mammal, the method comprising administering to a mammal in need thereof a composition comprising a peptide consisting of the amino acid sequence X1X2X3X4X5X6X7X8, wherein:
- X1 is a hydrogen or an amino-terminal blocking group;
- X2 is an amino acid selected from the group consisting of D, E, H, K, and R;
- X3 is an amino acid selected from the group consisting of D and E;
- X4 is an amino acid selected from the group consisting of I, L, and V;
- X5 is an amino acid selected from the group consisting of I, L, and V;
- X6 is an amino acid selected from the group consisting of M;
- X7 is an amino acid selected from the group consisting of D, E, H, K, and R;
- and
- X8 is hydrogen or a carboxyl-terminal blocking group.
A method of inhibiting PAI-1-dependent adhesion of a cell to a tissue of a mammal, the method comprising administering to the tissue a composition comprising a peptide consisting of the amino acid sequence X1X2X3X4X5X6X7X8, wherein:
- X1 is a hydrogen or an amino-terminal blocking group;
- X2 is an amino acid selected from the group consisting of D, B, H, K, and R;
- X3 is an amino acid selected from the group consisting of D and B;
- X4 is an amino acid selected from the group consisting of I, L, and V;
- X5 is an amino acid selected from the group consisting of I, L, and V;
- X6 is an amino acid selected from the group consisting of M;
- X7 is an amino acid selected from the group consisting of D, B, H, K, and R;
- and
- X8 is hydrogen or a carboxyl-terminal blocking group, to inhibit adhesion of the cell to said tissue.
A method of promoting clearance of scuPA from the surface of a mammalian cell, the method comprising administering to the cell an effective amount of a composition comprising a peptide consisting of the amino acid sequence X1X2X3X4X5X6X7X8, wherein:
- X1 is a hydrogen or an amino-terminal blocking group;
- X2 is an amino acid selected from the group consisting of D, E, H, K, and R;
- X3 is an amino acid selected from the group consisting of D and E;
- X4 is an amino acid selected from the group consisting of I, L, and V;
- X5 is an amino acid selected from the group consisting of I, L, and V;
- X6 is an amino acid selected from the group consisting of M;
- X7 is an amino acid selected from the group consisting of D, E, H, K, and R;
- and
- X8 is hydrogen or a carboxyl-terminal blocking group;
- to promote clearance of the scuPA from the cell.
A method of inhibiting PAI-1 activity in a tissue of a mammal, the method comprising administering to the tissue an effective amount of a composition comprising a peptide consisting of the amino acid sequence X1X2X3X4X5X6X7X8, wherein:
- X1 is a hydrogen or an amino-terminal blocking group;
- X2 is an amino acid selected from the group consisting of D, E, H, K, and R;
- X3 is an amino acid selected from the group consisting of D and E;
- X4 is an amino acid selected from the group consisting of I, L, and V;
- X5 is an amino acid selected from the group consisting of I, L, and V;
- X6 is an amino acid selected from the group consisting of M;
- X7 is an amino acid selected from the group consisting of D, E, H, K, and R;
- and
- X8 is hydrogen or a carboxyl-terminal blocking group, to inhibit PAI-1 activity in the tissue.
A composition comprising a combination of a peptide consisting of the amino acid sequence X1X2X3X4X5X6X7X8, wherein:
- X1 is a hydrogen or an amino-terminal blocking group;
- X2 is an amino acid selected from the group consisting of D, E, H, K, and R;
- X3 is an amino acid selected from the group consisting of E and D;
- X4 is an amino acid selected from the group consisting of I, L, and V;
- X5 is an amino acid selected from the group consisting of I, L, and V;
- X6 is an amino acid selected from the group consisting of M;
- X7 is an amino acid selected from the group consisting of D, E, H, K, and R;
- and
- X8 is hydrogen or a carboxyl-terminal blocking group,
- and a thrombolytic agent.
A composition comprising a combination of peptide consisting of the amino acid sequence X1X2X3X4X5X6X7X8, wherein:
- X1 is a hydrogen or an amino-terminal blocking group;
- X2 is an amino acid selected from the group consisting of D, E, H, K, and R;
- X3 is an amino acid selected from the group consisting of E and D;
- X4 is an amino acid selected from the group consisting of I, L, and V;
- X5 is an amino acid selected from the group consisting of I, L, and V;
- X6 is an amino acid selected from the group consisting of M;
- X7 is an amino acid selected from the group consisting of D, E, H, K, and R;
- and
- X8 is hydrogen or a carboxyl-terminal blocking group,
- and an anti-coagulating agent.
Dependencies are inferred from the claim text.