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First Insight on Small Molecules as Cardiac Calsequestrin Stabilizers.

ABSTRACT: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations of cardiac calsequestrin (CASQ2) that impair its characteristic ability of Ca2+-induced polymerization-depolymerization. However, stabilizing the CASQ2 polymer by pharmacological agents to treat CPVT has not been reported so far. Here, we tested whether small molecules can stabilize CASQ2 polymers. We synthesized 24 glycinate/alaninate/acetate ?-pyranone analogs and conducted the CASQ2 depolymerization assay. Most of the molecules of this class of compounds inhibited the depolymerization of the protein upon Ca2+ chelation by ethylene glycol tetraacetic acid. Structure-activity relationship studies revealed that the compounds with the 4-fluoro-phenyl group at the C-6 position of the pyranone ring and open-chain primary amine at C-4 are the most active of the class. This is the first report of an ?-pyranone class of compounds with the ability to stabilize CASQ2 polymers and opens up the possibility to target Ca2+-release disorders via modulation of CASQ2 polymerization.

SUBMITTER: Chakravarty H

PROVIDER: S-EPMC6682146 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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First Insight on Small Molecules as Cardiac Calsequestrin Stabilizers.

Chakravarty Harapriya H Bal Chandralata C Yadav Monika M Jena Nivedita N Bal Naresh C NC Sharon Ashoke A

ACS omega 20190702 7

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations of cardiac calsequestrin (CASQ2) that impair its characteristic ability of Ca<sup>2+</sup>-induced polymerization-depolymerization. However, stabilizing the CASQ2 polymer by pharmacological agents to treat CPVT has not been reported so far. Here, we tested whether small molecules can stabilize CASQ2 polymers. We synthesized 24 glycinate/alaninate/acetate α-pyranone analogs and conducted the CASQ2 depolymerization ...[more]

PMID: 31460256

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Project description:Over decades dependency of humans on the drugs has become indispensable and irreplaceable. Thus, each year many new drugs are licensed. Nonetheless, drugs undergo rigorous testing and analysis to be available globally in economic price for the suitability of patients with different age and physiological conditions. The testing of drugs include phase I clinical trial using small group of 20–100 healthy volunteers for safety, pharmacology and efficacy; phase II clinical trial using 100–500 volunteer patients to optimize effective dose, dose interval, safety analysis and mode of delivery such as oral or intravenous; phase III clinical trial using 1000–5000 in a larger population of patients globally at different international places to collect sufficient safety and efficacy data for patenting and licencing. Moreover, thousands of drugs fail to achieve these objectives. Therefore, this mini-review intends to critically examine and assimilate the clinical applications of selected complex repurposed small drug molecules which are in different phase of trials for treating viral infection including complications due to COVID-19: (a) Remdesivir, (b) Galidesivir, (c) Favipiravir, (d) Baricitinib, and (e) Baloxavir. Graphical abstract Image 1 Over decades dependency of humans on the drugs has become indispensable and irreplaceable. Thus, each year many new drugs are licensed. Nonetheless, drugs undergo rigorous testing and analysis to be available globally in economic price for the suitability of patients with different age and physiological conditions. The testing of drugs include phase I clinical trial using small group of 20–100 healthy volunteers for safety, pharmacology and efficacy; phase II clinical trial using 100–500 volunteer patients to optimize effective dose, dose interval, safety analysis and mode of delivery such as oral or intravenous; phase III clinical trial using 1000–5000 in a larger population of patients globally at different international places to collect sufficient safety and efficacy data for patenting and licencing. Moreover, thousands of drugs fail to achieve these objectives. Therefore, this mini-review intends to critically examine and assimilate the clinical applications of selected complex repurposed small drug molecules which are in different phase of trials for treating viral infection including complications due to COVID-19: (a) Remdesivir, (b) Galidesivir, (c) Favipiravir, (d) Baricitinib, and (e) Baloxavir. Graphical abstract Image 1

Dataset Information

First Insight on Small Molecules as Cardiac Calsequestrin Stabilizers.

Publications

First Insight on Small Molecules as Cardiac Calsequestrin Stabilizers.

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