Structurally Simple, Readily Available Peptidomimetic 1-Benzyl-5-methyl-4-( n-octylamino)pyrimidin-2(1 H)-one Exhibited Efficient Cardioprotection in a Myocardial Ischemia (MI) Mouse Model.

Abstract

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.

• Authors: Lena Trifonov, Vadim Nudelman, Michael Zhenin, Erez Matsree, Michal Afri, Bruria Schmerling, Guy Cohen, Krzysztof Jozwiak, Michal Weitman, Edward Korshin, Hanoch Senderowitz, Asher Shainberg, Edith Hochhauser, Arie Gruzman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 24 Pg. 11309-11326 (12 27 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30507195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• IL1B protein, rat
• Interferon Regulatory Factors
• Interleukin-1beta
• Peptidomimetics
• Pyrimidines
• Tlr4 protein, rat
• Toll-Like Receptor 4

Topics

• Animals
• Binding Sites
• Cardiotonic Agents (chemistry, metabolism, pharmacology)
• Cell Hypoxia (drug effects)
• Computer Simulation
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Design
• Interferon Regulatory Factors (metabolism)
• Interleukin-1beta (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Myocardial Ischemia (drug therapy, metabolism, pathology)
• Myocytes, Cardiac (drug effects, pathology)
• Peptidomimetics (chemistry, pharmacology)
• Pyrimidines (chemistry, metabolism, pharmacology)
• Rats, Sprague-Dawley
• Toll-Like Receptor 4 (chemistry, genetics, metabolism)