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Updated: Aug 2, 2025
10:28
A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors
Published on: August 17, 2019
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Drug discovery for heart failure targeting myosin-binding protein C
Biorxiv : the Preprint Server for Biology
|April 17, 2023
Summary
Researchers identified small molecules targeting cardiac MyBP-C (cMyBP-C) to potentially treat heart failure (HF). These compounds modulate cMyBP-C
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- Cardiac MyBP-C (cMyBP-C) regulates cardiac muscle contractility by interacting with actin and myosin.
- Reduced cMyBP-C phosphorylation in heart failure (HF) impairs cardiac function, making cMyBP-C a therapeutic target.
- Developing drugs that mimic phosphorylation or alter cMyBP-C interactions is a promising strategy for HF treatment.
Approach:
- Utilized high-throughput screening (HTS) with fluorescence lifetime (FLT) detection to identify small molecules.
- Labeled actin and the cMyBP-C C0-C2 fragment with distinct fluorescent probes (FMAL and TMR).
- Performed complementary assays to detect binding to cMyBP-C and its interaction with actin/myosin.
Key Points:
- Identified compounds that bind to cMyBP-C and modulate its interaction with actin/myosin.
- Secondary assays confirmed compound specificity for phosphorylated cMyBP-C and differentiated effects on cardiac vs. skeletal muscle.
- A subset of compounds altered ATPase activity in cardiac and skeletal myofibrils.
Conclusions:
- Established a feasible HTS platform for discovering modulators of the cMyBP-C-actin/myosin interaction.
- Demonstrated the potential for small molecules to target cMyBP-C for novel heart failure therapies.
- This work paves the way for developing new treatments for cardiovascular diseases.
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