Inhibiting collagen-induced platelet aggregation and activation with peptide variants
The present invention provides peptides consisting of L- and/or D-amino acids and combinations thereof, which affect platelets by action on the collagen receptor, glycoprotein VI (GPVI). More specifically, however, the peptides act on the GPVI-FcRγ signaling complex. The invention also provides lipid and sugar conjugated peptides comprising L- or D-amino acids. The invention still further provides a method of designing of the peptides and lipid- and/or sugar-conjugated peptides comprising L- or D-amino acids. The present invention further relates to the therapy of various disease states involving the use of these peptides and compounds. Specifically, the peptides and compounds are useful in the treatment and/or prevention of a disease or condition involving platelet activation and aggregation, and more particularly, collagen-induced platelet activation and aggregation. They also are useful in the production of medical devices comprising peptide matrices (i.e., for example, cardiovascular stents).
1. A method comprising:
a) providing;
i) a patient having a medical condition resulting from platelet aggregation; and
ii) a peptide consisting of the amino acid sequence of G-N-L-V-R-I-X 1 -X 2 -X 3 -A-X 4 -X 5 -X 6 -X 7 -I (SEQ ID NO: 1), wherein X 1 is selected from the group consisting of C, L or G; X 2 is selected from the group consisting of L or A; X 3 is selected from the group consisting of G or R; X 4 is selected from the group consisting of V or I; X 5 is selected from the group consisting of I, L or R; X 6 is selected from the group consisting of I or L; and X 7 is selected from the group consisting of I or L capable of reducing platelet aggregation;
b) administering said inhibitor to said patient under conditions such that said platelet aggregation is reduced.
2. The method of claim 1 , wherein said medical condition comprises a collagen-induced platelet disorder.
3. The method of claim 2 , wherein said platelet disorder is selected from the group consisting of atherosclerosis, coronary artery disease, ischemic cerebrovascular disease, peripheral vascular disease, diabetes mellitus, renal disease, inflammatory bowel disease, asthma, cystic fibrosis, rheumatoid arthritis, Kawasaki disease, tumor growth and metastasis, Alzheimer's disease, psychiatric disorders, thrombocytopenia, platelet function defects, von Willebrand disease, immune thrombocytopenia purpura, and inherited and acquired disorders of platelet function.
4. The method of claim 1 , wherein at least one amino acid of the peptide is substituted by a D-amino acid.
5. The method of claim 1 , wherein the peptide is conjugated to an N-terminal sugar conjugate.
6. The method of claim 1 , wherein the peptide is conjugated to a C-terminal lipid conjugate.
7. The method of claim 5 , wherein said sugar conjugate is 1-amino-glucose succinate.
8. The method of claim 6 , wherein said lipid conjugate is selected from at least one of the group consisting of Gly-Tris-monopalmitate, Gly-Tris-dipalmitate, Gly-Tris-tripalmitate, 2-aminododecanoate, and myristoylate conjugates.