Structurally Simple, Readily Available Peptidomimetic 1-Benzyl-5-methyl-4-(n-octylamino)pyrimidin-2(1H)-one Exhibited Efficient Cardioprotection in a Myocardial Ischemia (MI) Mouse Model
| Autor: | Michal Weitman, Lena Trifonov, Bruria Schmerling, Arie Gruzman, Michal Afri, Hanoch Senderowitz, Guy Cohen, Edward E. Korshin, Vadim Nudelman, Erez Matsree, Michael Zhenin, Asher Shainberg, Edith Hochhauser, Krzysztof Jozwiak |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cardiotonic Agents Peptidomimetic Interleukin-1beta Myocardial Ischemia Inflammation Pharmacology Interleukin-1 receptor 010402 general chemistry 01 natural sciences Rats Sprague-Dawley 03 medical and health sciences Drug Discovery medicine Animals Computer Simulation Myocytes Cardiac Receptor Cardioprotection Binding Sites Dose-Response Relationship Drug Chemistry Pattern recognition receptor Cell Hypoxia 0104 chemical sciences Mice Inbred C57BL Toll-Like Receptor 4 Disease Models Animal Pyrimidines 030104 developmental biology TRIF Drug Design Interferon Regulatory Factors TLR4 Molecular Medicine Peptidomimetics medicine.symptom |
| Zdroj: | Journal of Medicinal Chemistry. 61:11309-11326 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01471 |
| Popis: | TLR4, a member of the Toll-like receptor (TLR) family, serves as a pattern recognition receptor in the innate immune response to microbial pathogens. TLR4 also regulates the inflammatory reaction to ischemic injury in the heart. The TRIF-related adaptor molecule (TRAM) is an adapter that recruits the Toll/interleukin 1 receptor (TIR) domain, which contains adapter-inducing IFN-β (TRIF), to activate TLR4, following TRIF-dependent cytokine gene transcription. On the basis of a known TRAM-derived decoy peptide, 10 of its peptidomimetics were synthesized. One of them, 1-benzyl-5-methyl-4-( n-octylamino)pyrimidin-2(1 H)-one (21), exhibited high potency and efficacy in vitro. In vitro results and in silico analysis provided evidence for the possible direct interaction of 21 with the TLR4 complex. Administered in mice, 21 was able to block the pathophysiological manifestation of MI, restoring the concomitant tissue damage, with a 100% survival rate. Thus, inhibition of TLR4-mediated inflammation in postischemic myocardium could be used as an approach for developing cardioprotective drugs. |
| Databáze: | OpenAIRE |
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