Fixing A Problematic Medicine, Plavix First and Stereoselective Chemical Synthesis of the Intricate Active Metabolite for Overcoming Its Prominent Clinical Resistance and Elucidating Its Unique Action of Sequential Cysteine Modification and GPCR Signaling

Speaker: 
Dr. Yaoqiu Zhu, Assistant Professor, Dept. of Chemistry & Biochemistry, The University of Texas at El Paso
Location: 
Zoom
Date / Time: 
Thursday, May 6, 2021 - 4:00pm
Host: 
Dr. Ryan A. Altman
Abstract: 

Despite of being one of the most prescribed medicines in history, the serendipitous prodrug clopidogrel (CPG, Plavix) remains to be the mysterious and problematic antiplatelet to patients and a puzzling and formidable subject to researchers. The elusive active metabolite of CPG, H4, is reactive and unstable, and its structure and mechanism of action have yet to be fully elucidated. On the other hand, clinical CPG treatment has been associated with a daunting level of resistances, which is due to the fact that large populations of patients cannot metabolize it to H4. The lack of comprehensive response predictives and superior treatment alternatives, together with the life-threatening nature of thrombotic ischemia, have made H4 a high-profile synthetic target. However, the long pursuit of the intricate degradation structure proves to be challenging and remains unsolved. This seminar will present a 10-step first and stereoselective chemical synthesis of H4 that is enabled by a series of nontraditional approaches. Synthetic H4, with an elucidated bioactive configuration, has demonstrated stereospecific potency in vivo and can be flexibly stabilized to releasable forms for clinical applications. H4 is a rare inhibitor bearing a sulfhydryl group, and model studies have revealed an intriguing case of mercapto activation as the result of an unprecedented SN2 reaction, which can lead to a sequential cysteine modification of persulfidation. These results suggest that the thiophene S-atom in CPG can be metabolically activated to free sulfides via two pathways for signaling the versatile GPCR of P2Y12 receptor. This integrative research does not only solve the long overdue clinical conundrums of CPG but also demonstrates that clinical drugs can be a good starting point for developing revitalized or repurposed medicines and for acquiring human subject-derived new sciences.

 
S-atom

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