A Potent Fluorescent Reversible-Covalent Inhibitor of Cardiac Muscle Contraction

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2021 Sep 17

PMID 34531960

Authors

Fangze Cai

Thomas Kampourakis

Brittney A Klein

Brian D Sykes

Affiliations

Soon will be listed here.

Abstract

Compounds that directly modulate the response of the cardiac sarcomere have potential in the treatment of cardiac disease. While a number of sarcomere activators have been discovered and extensively studied, very few inhibitors have been identified. We report a potent cardiac sarcomere inhibitor, DN-F01, targeting the cardiac muscle thin filament protein troponin complex. Functional studies show that DN-F01 has a strong inhibitory calcium-dependent effect on cardiac myofibrillar ATPase activity with an IC value of 11 ± 4 nmol/L. DN-F01 is shown to bind to a cardiac troponin C-troponin I chimera (cChimera) with a of ∼50 nM using fluorescence spectroscopy, indicating that troponin is the likely target for DN-F01. NMR titrations of DN-F01 to C35S and A-Cys cChimera show covalent and noncovalent binding of DN-F01 bound to the calcium-saturated cChimera.

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