Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction.

ABSTRACT: Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant K_D of 6-24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (K_D 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa₅₀ of isometric contraction from 6.28 to 6

SUBMITTER: Mahmud Z 

PROVIDER: S-EPMC9213791 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature