Small molecules modulating force production: A new perspective against myosin-associated diseases.

Abstract

Myosins are ATP-dependent molecular motors involved in almost all processes of life. These motors are associated with various human diseases such as various cardiomyopathies, spasticity, deafness or malaria. Nowadays, the most promising approach to treat myosin-associated diseases is the design of small-molecule drugs able to specifically modulate the force produced by these motors. Camzyos (mavacamten) is a specific inhibitor recently approved by the FDA to treat adults with symptomatic class II-III obstructive hypertrophic cardiomyopathy. Omecamtiv mecarbil (OM) also targets β-cardiac myosin but in this case, it is an activator of contraction, currently in late Phase 3 for heart failure. Here we present how a methodology combining X-ray crystallography, molecular dynamics and functional assays allows to study the mechanism of action of some of these compounds. We have determined that despite their antagonistic effects on force production, OM and Mava surprisingly target the same pocket. MPH-220 is a Blebbistatin derivative identified as an inhibitor of skeletal myosin-2 (SkMyo2) and a promising treatment against muscle spasticity. Structures of other inhibitors bound in this pocket with distinct IC50 for three muscle myosins have also provided clues about the parameters that control potency and specificity. KNX-002 is a new inhibitor of Plasmodium falciparum myosin A (PfMyoA). PfMyoA is essential for both red blood cells invasion and parasite motility and is a first-order pharmacological target against malaria. Our structure of PfMyoA complexed to KNX-002 shows how the inhibitor selectively targets an undescribed pocket in the motor, sequestering the myosin in a state detached from actin and preventing hydrolysis. Altogether, these results show how small molecules modulating the force produced by myosins are promising avenues to treat myosin-associated diseases and opens up new approaches to the design of more selective and potent compounds.