Design and Evaluation of Nonpeptide Fibrinogen .gamma. Chain-Based GPIIB/IIIA Antagonists
| Autor: | Beavers Mp, William J. Hoekstra, Kloczewiak M, Mayo Kh, Evangelisto Mf, Press Jb, Tomko Ka, Patricia Keane, Patricia Andrade-Gordon, Francis Fan |
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| Rok vydání: | 1995 |
| Předmět: |
Fibrinogen-gamma chain
chemistry.chemical_classification Magnetic Resonance Spectroscopy biology Fibrinogen receptor Chemistry Molecular Sequence Data Integrin Fibrinogen Fibrinogen binding Peptide Platelet Membrane Glycoproteins Thrombin Biochemistry Drug Design Drug Discovery biology.protein medicine Humans Molecular Medicine Amino Acid Sequence Binding site Platelet Aggregation Inhibitors medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 38:1582-1592 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Two series of nonpeptide turn mimetics were designed by analysis of the solution NMR structure of the 385-411 sequence of the y-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most interesting compound from our study, RWJ 50042 (25), exhibits potent inhibition of fibrinogen binding to GPIIbDIIa (ICs0 = 0.009 pM), as well as thrombin- or collagen-induced platelet aggregation (ICs0 = 0.76, 0.14 pM). Since the 400-411 sequence is required for y-chain bioactivity and is a unique recognition sequence among ligands for integrins, vis-a-vis other RGD (Arg-Gly-Aspbpresenting proteins, these turn mimetics may represent a new, selective approach to antagonism of the fibrinogen receptor. Platelet aggregation constitutes an important response to curtail bleeding induced by vascular injury. However, pathological extension of this normal hemostatic process can lead to total occlusion of a vessel. Platelet aggregation is mediated by fibrinogen binding to platelet receptor glycoprotein IIbAIIa (GPIIbAIIa). Because this binding is the final common pathway leading to platelet aggregation, a fibrinogen receptor antagonist has become well-recognized as a potentially useful drug in the treatment of thrombotic disorders. Fibrinogen interacts with binding sites on GPIIbAIIa through peptide domains present on the a- and y-chains: RGDF (Arg-Gly-Asp-Phe, a95-98), RGDS (Arg-Gly-AspSer, a572-5751, and HHLGGAKQAGDV (His-His-LeuGly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val, 112 Although the RGD motifs and the y-chain dodecapeptide appear to have unique binding sites on GPIIbAIIa (i.e., 109-171 of IIIa and 294-314 of IIb, respectively), the RGD binding site is not mutually exclusive from the dodecapeptide site, which implies either cross-binding or close proximity of these two sites.3 In our biochemical assays, RGDS and HHLGGAKQAGDV have comparable ICs0 values for the inhibition of fibrinogen binding to immobilized GPIIbAIIa, 1.0 and 4.1 pM, respectively |
| Databáze: | OpenAIRE |
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