Open AccessA Potent Fluorescent Reversible-Covalent Inhibitor of Cardiac Muscle Contraction
Author(s) -
Fangze Cai,
Thomas Kampourakis,
Brittney A. Klein,
Brian D. Sykes
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00366
Subject(s) - sarcomere , myofibril , troponin i , troponin , covalent bond , cardiac muscle , chemistry , gene isoform , calcium , biochemistry , medicine , biophysics , myocyte , biology , microbiology and biotechnology , organic chemistry , myocardial infarction , gene
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 50 value of 11 ± 4 nmol/L. DN-F01 is shown to bind to a cardiac troponin C-troponin I chimera (cChimera) with a K D 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.