Skeletal muscle relaxant development

Development of a highly specific skeletal muscle relaxant directly acting on the myosin motor protein

Current muscle relaxants and spasmolytics act on the central nervous system or on the neuromuscular junctions and thus can have severe side effects like heart failure and paralysis.

A specific drug directly acting on the motor unit (myosin 2) of skeletal muscles would be of high importance and of immediate clinical need.

We designed, synthesized and purified a small molecule myosin inhibitor that is highly selective for skeletal muscle myosin 2 while influencing neither cardiac nor smooth nor non-muscle myosin 2 activities.

Atomic resolution structure of the central part of muscle contraction: the actomyosin complex. The structure represents the myosin head fragment (dark blue) with a bound light chain (yellow) in an actin filament (light blue and green monomers) attached state. Our myosin inhibitors can block myosin’s enzymatic cycle in an actin detached state thereby avoiding actomyosin contraction, which consequently leads to relaxation of muscles.

The molecular basis for this selectivity is a single amino acid difference among myosin 2 isoforms: skeletal muscles of most species contain a small amino acid sidechain where all other myosin 2 isoforms have a bulkier one at this position. Our specific inhibitor contains a bulky chemical group, which creates a steric hindrance when interacting with smooth, cardiac or non-muscle myosin 2, but can optimally fit into the binding pocket of skeletal muscle myosin 2.

Our new skeletal specific inhibitor is highly soluble and non-mutagenic providing optimal properties for further drug development.