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Journal article
Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodelling and heart failure
Cardiovascular research, v 118(7), pp 1771-1784
16 Jun 2021
PMID: 34132787
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Aims Hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by post-translational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling. Here, the aim of this study was to discover a first-in-class inhibitor of human SQOR and evaluate its cardioprotective effect in an animal model of HFrEF. Methods and results We identified a potent inhibitor of human SQOR (STI1, IC50 = 29 nM) by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibited very low cytotoxicity and attenuated the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors. A mouse HFrEF model was produced by transverse aortic constriction (TAC). Treatment of TAC mice with STI1 mitigated the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreased the pressure gradient across the aortic constriction. Moreover, STI1 dramatically improved survival, preserved cardiac function, and prevented the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy. Conclusion We demonstrate that the coenzyme Q-binding pocket in human SQOR is a druggable target and establish proof of concept for the potential of SQOR inhibitors to provide a novel therapeutic approach for the treatment of HFrEF.
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Details
- Title
- Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodelling and heart failure
- Creators
- Michael R. Jackson - Drexel UniversityKristie D. Cox - Drexel UniversitySimon D. P. Baugh - Fox Chase Chemical Diversity CenterLuke Wakeen - Drexel UniversityAdel A. Rashad - Drexel UniversityPatrick Y. S. Lam - Fox Chase Chemical Diversity CenterBoris Polyak - Drexel UniversityMarilyn Schuman Jorns - Drexel University
- Publication Details
- Cardiovascular research, v 118(7), pp 1771-1784
- Publisher
- Oxford Univ Press
- Number of pages
- 14
- Grant note
- GM107389 / National Institute of General Medical Sciences at the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R41 HL134435 / National Heart, Lung, and Blood Institute at the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Coulter-Drexel Translational Research Partnership Awards
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Pharmacology and Physiology; [Retired Faculty]; Surgery
- Web of Science ID
- WOS:000755869900001
- Scopus ID
- 2-s2.0-85119144781
- Other Identifier
- 991019168227704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cardiac & Cardiovascular Systems