What is the clinical evidence from this study?

Population: Heart failure. Intervention: 1280-compound library screen. Primary outcome: Reduction in C0-C2 binding to actin.

What question did this study set out to answer?

This research aims to identify small-molecule inhibitors that disrupt the interaction between cMyBP-C and actin, facilitating new heart failure treatments.

May 28, 2021Journal of Biological ChemistryOpen Access

Cardiac myosin-binding protein C interaction with actin is inhibited by compounds identified in a high-throughput fluorescence lifetime screen

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Key result

A high-throughput fluorescence lifetime screen identified three compounds (suramin, NF023, and aurintricarboxylic acid) that reduced cMyBP-C binding to actin in the micromolar range.

Why the study?

Heart failure patients often show decreased cMyBP-C phosphorylation, making cMyBP-C a potential target for therapeutics that mimic phosphorylation or disrupt actin/myosin interactions.

Population

1280-compound library tested with fluorescent dye-labeled actin and cMyBP-C N-terminal fragment C0-C2

Comparison

Small-molecule library screening for inhibition of actin-cMyBP-C binding

Design

High-throughput fluorescence lifetime-based assay screen

Authors

TBThomas A. BunchUniversity of Arizona PGPiyali GuhathakurtaUniversity of Minnesota VLVictoria C. LepakHeart Failure / Cardiomyopathy

Discussion

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Implication

Requires preclinical validation in heart failure models before clinical exploration; leaves open whether cMyBP-C-actin inhibition is a viable target.

Key Points

This research aims to identify small-molecule inhibitors that disrupt the interaction between cMyBP-C and actin, facilitating new heart failure treatments.
Utilized a fluorescence lifetime-based assay to screen a library of 1280 compounds.
Performed actin labeling with a fluorescent dye near cMyBP-C binding sites.
Conducted binding assays, including TR-FRET, ITC, and TPA, to confirm inhibitor efficacy.
Identified three compounds (suramin, NF023, aurintricarboxylic acid) that reduced C0-C2 binding to actin in the micromolar range.
Phosphorylated C0-C2 binding was blocked by these compounds.
Compounds specifically bind to cMyBP-C and inhibit its interaction with actin, confirmed through multiple assays.

Structured PICO

Population

In vitro model using actin labeled with a fluorescent dye (Alexa Fluor 568) and cardiac myosin-binding protein C (cMyBP-C) N-terminal fragment (C0-C2)

Intervention

High-throughput screen of a 1280-compound library

Outcome

Reduction in fluorescence lifetime of AF568-actin as a readout of actin bindingsurrogate

A novel fluorescence lifetime-based assay successfully identified small-molecule inhibitors of actin-cMyBP-C binding, providing a validated high-throughput screen for potential heart failure therapeutics.

Cite This Study

Bunch et al. (2021) studied Heart failure. 1280-compound library screen was evaluated on Reduction in C0-C2 binding to actin. A high-throughput fluorescence lifetime screen identified three compounds (suramin, NF023, and aurintricarboxylic acid) that reduced cMyBP-C binding to actin in the micromolar range.

synapsesocial.com/papers/6a6a1530ba3b67e10e4489cb https://doi.org/10.1016/j.jbc.2021.100840

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Implication

Requires preclinical validation in heart failure models before clinical exploration; leaves open whether cMyBP-C-actin inhibition is a viable target.

Cardiac myosin-binding protein C interaction with actin is inhibited by compounds identified in a high-throughput fluorescence lifetime screen

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Cardiac myosin-binding protein C interaction with actin is inhibited by compounds identified in a high-throughput fluorescence lifetime screen

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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