RESEARCH ARTICLE
Influence of Aromatic and Aliphatic Moieties on Thrombin Inhibitors Potency
Alexey Poyarkov*, 1, Xavier Rocabayera2, Svetlana Poyarkova1, Valery Kukhar1
Article Information
Identifiers and Pagination:
Year: 2008Volume: 2
First Page: 143
Last Page: 149
Publisher ID: TOBIOCJ-2-143
DOI: 10.2174/1874091X00802010143
Article History:
Received Date: 28/9/2008Revision Received Date: 10/10/2008
Acceptance Date: 13/10/2008
Electronic publication date: 18/11/2008
Collection year: 2008
open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
Abstract
Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. To design the efficient thrombin inhibitors we have synthesized and studied peptide-based inhibitors resistant to enzymatic degradation. Compounds with general formula X-DArg-D-Phe-OMe, where X = residue of 3-[6-ethyl-7-hydroxy-3-(4-methyl-thiazol-2-yl)-4-oxo-4H-chromen-2-yl]-propionic acid (chromone) and lauric acid were synthesized by classic methods of peptides synthesis in solution. The comparative inhibitory analysis of prepared compounds in relation to thrombin was conducted. The analysis of the inhibition effect of the peptide with retro-D-sequence modified by residues of natural organic compounds (chromone or fatty acid moiety) has demonstrated that modification with the fatty acid residue appeared to be the most successful one. Introduction of lauric acid residue (Ki = 1,76 μM) maximally increased the inhibition effect. These findings establish an important role of fatty moiety in structure of inhibitors in preferential binding and inhibition of thrombin active side.
