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Cyclic RGD peptide analogues as antiplatelet antithrombotics
P L Barker1, S Bullens, S Bunting
1Bioorganic Chemistry, Genentech, Inc., South San Francisco, California 94080.
Journal of Medicinal Chemistry
|May 29, 1992
Summary
Researchers developed novel cyclic peptides that inhibit platelet aggregation by targeting GPIIbIIIa. One compound, G-4120, shows potent antithrombotic activity, comparable to natural inhibitors, making it a promising candidate for acute therapy.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Platelet aggregation, mediated by GPIIbIIIa binding fibrinogen, is crucial for thrombus formation.
- Inhibitors of GPIIbIIIa/fibrinogen interaction are potential antithrombotic agents for acute conditions.
Purpose of the Study:
- To synthesize and evaluate novel cyclic peptides incorporating the Arg-Gly-Asp (RGD) sequence as GPIIbIIIa/fibrinogen antagonists.
- To identify potent antithrombotic candidates for further investigation.
Main Methods:
- Solid-phase peptide synthesis of RGD-containing cyclic peptides with thioether or sulfoxide bridges.
- Evaluation using GPIIbIIIa ELISA and platelet aggregation assays.
- Comparison with kistrin, a known snake venom inhibitor.
Main Results:
- A series of cyclic peptides, including thioether- and sulfoxide-bridged variants, were successfully synthesized.
- The sulfoxide-bridged cyclic peptide G-4120 demonstrated potent inhibition of platelet aggregation.
- G-4120 exhibited equipotent antithrombotic activity to kistrin (IC50 = 0.15 microM).
Conclusions:
- Novel cyclic RGD peptides can effectively inhibit GPIIbIIIa-mediated platelet aggregation.
- G-4120 is a potent antithrombotic agent with potential for clinical application in thrombotic disorders.