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Drug discovery for heart failure targeting myosin-binding protein C
Thomas A Bunch1, Piyali Guhathakurta2, Andrew R Thompson2
1Department of Cellular & Molecular Medicine, University of Arizona, Tucson, Arizona, USA.
The Journal of Biological Chemistry
|October 21, 2023
Summary
Researchers discovered small molecules that modulate cardiac MyBP-C (cMyBP-C) interactions with actin and myosin. These compounds show potential for developing new heart failure (HF) therapies by targeting cMyBP-C function.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- Cardiac MyBP-C (cMyBP-C) regulates cardiac muscle contractility by interacting with actin and myosin.
- Decreased cMyBP-C phosphorylation is linked to heart failure (HF) and is cardioprotective in HF models.
- Modulating cMyBP-C interactions presents a therapeutic strategy for HF.
Purpose of the Study:
- To identify small molecules that bind to cMyBP-C and alter its interaction with actin or myosin.
- To establish a high-throughput screening (HTS) platform for discovering cMyBP-C modulators.
- To pave the way for novel HF drug development targeting cMyBP-C.
Main Methods:
- Utilized fluorescence lifetime (FLT) detection with labeled actin and cMyBP-C fragments (cC0-C2) in two complementary HTS assays.
- Employed Förster resonance energy transfer (FRET) to measure binding between cMyBP-C and actin.
- Assessed compound binding directly to cC0-C2 and evaluated specificity for phosphorylated/unphosphorylated forms and cross-reactivity with skeletal MyBP-C.
Main Results:
- Successfully established HTS assays to discover small molecules targeting cMyBP-C.
- Identified compounds that bind to cMyBP-C and modulate its interaction with actin.
- A subset of compounds affected myofibril ATPase activity, indicating functional impact.
Conclusions:
- Demonstrated the feasibility of discovering small-molecule modulators of the cMyBP-C-actin/myosin interaction.
- These findings support cMyBP-C as a viable drug target for heart failure.
- The developed HTS platform can accelerate the identification of novel HF therapeutics.
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