Understanding how cardiac myosin modulators regulate function in health and disease

Start date: 13 April 2025
End date: 12 April 2028
Value: £711,642.02
Primary investigator: Dr Charlie Scarff
Co-investigators: Stephen Muench
External co-investigators: Dr Anton Calabrese (The Astbury Centre for Structural Molecular Biology, University of Leeds)

Description

Cardiac myosin is the molecular motor that drives heart contraction, powered by the energy-source ATP and through its interaction with actin tracks. Direct modulators of cardiac myosin function are promising treatments for inherited heart disease and heart failure. Current treatments improve heart function but not patient survival. Direct myosin modulators have the potential to do both.

A first-in-class cardiac myosin inhibitor, Mavacamten, was approved by the FDA for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in 2022. Whilst the muscle activator Omecamtiv mecarbil (OM) has been shown to improve cardiac function in patients with systolic heart failure, modestly decreasing heart-failure events and deaths in a Phase III trial.

Consequently, the potential use of direct myosin modulators for the long-term treatment of various muscle diseases has been more broadly recognised and many other myosin modulators have entered clinical trials. Critically, despite a range of pre-clinical studies, we still have very little idea as to how these modulators work at the molecular level, which hinders their clinical usage and development.

In this project, we will study the effects of modulators on myosin structure, dynamics and function using cryo electron microscopy, structural mass spectrometry approaches and kinetic assays. With this structural, dynamic, and functional knowledge, we will predict the effects of these modulators on myosin function in the presence of HCM disease-causing mutations and test these predictions for specific mutations. This will provide unprecedented detail of the effects of the modulators mavacamten and OM on the cardiac myosin functional cycle in health and disease, provide an experimental pipeline for the assessment of the molecular mode of action of other modulators, currently in clinical trials, and for the structure-guided design of improved myosin modulators with the potential for improved patient outcomes.