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Treatment against heart insufficiencies: Unveiling how a cardiac muscle activator binds the motor and increase force production output.

A number of widespread and debilitating diseases, including heart failure, asthma, and various neuromuscular conditions are due to defects in muscle function. For more than a century, scientists have actively sought to develop treatments to improve the function of muscle in these diseases, and the need for such drugs continues to increase. For example, more than 20 million patients have chronic heart failure with at least 4 million admissions to hospital each year in the USA and Europe, and the size of this patient population is actively growing. Once hospitalized for heart failure, mortality rates at 30 days, 1 year, and 5 years were as high as 10%, 22%, and 42% in patients from four United States communities (1).

Cytokinetics, Incorporated (“Cytokinetics,” San Francisco, US) discovered and initiated development of omecamtiv mecarbil, a novel activator of cardiac myosin, the motor protein that powers cardiac muscle contraction. Omecamtiv mecarbil is a selective, small-molecule currently being studied in a Phase 3 clinical trial of ~8000 patients as a potential treatment for heart failure with reduced ejection fraction in collaboration with Amgen and in partnership with Servier. The structural basis for how omecamtiv mecarbil enhances the force generated by cardiac myosin is currently unknown.

Houdusse Lab
Coordinated contractions of cardiac muscle cells pump blood through the blood vessels of the circulatory system. Cardiac muscle cells have cross striations formed by the primary structural proteins of cardiac muscle, myosin and actin, organized into contractile units (sarcomeres). In this study, the atomic structure of the cardiac myosin motor domain has been solved with and without Omecamtiv mecarbil (magenta), an activator of force production. Omecamtiv mecarbil is found to bind the force-generating sub-domains of the cardiac myosin, readily explaining its mechanism of action.

Cardiac myosin consumes chemical energy, which it converts into force to power cardiac contraction. How binding of a small molecule can increase the performance of a muscle by promoting an increase in myosin motor force was unclear. The mechanism of action of omecamtiv mecarbil has now been elucidated by the Institut Curie team headed up by CNRS research director Anne Houdusse, in close collaboration with Cytokinetics, as recently published in Nature Communications (2). The atomic structures of the cardiac myosin motor domain, with and without bound omecamtiv mecarbil, were determined using X-ray crystallography. They reveal that the drug, omecamtiv mecarbil, does not change the motor mechanism nor does it influence its structure. Instead, omecamtiv mecarbil binds to an allosteric site that stabilizes states of the motor domain primed to interact with actin at the beginning of force production, thus increasing the number of motors that can participate in force production once the cardiac contraction cycle starts during systole.

Complementary collaborative work between Cytokinetics and the team headed by Anne Houdusse has also uncovered how highly specific small molecules can stop smooth muscle myosin activity. Their recent study, published in PNAS (3), characterizes the mechanism of action of a smooth muscle myosin inhibitor, CK-2018571, that induces smooth muscle relaxation and can be used to treat diseases involving smooth muscle hypercontractility, such as asthma and chronic obstructive pulmonary disease.

The work by the Houdusse team and Cytokinetics highlights how specific modulators of myosin activity have great potential to provide new treatments against human diseases. Molecular motors have major roles in cell proliferation, cell migration and tumor metastasis. The ongoing development of drugs that can target other classes of motors and characterization of their mechanism of action shows great promise for the development of anti-tumor drugs and treatment of other diseases caused by motor protein dysfunction.

  1. Loehr, L. R., Rosamond, W. D., Chang, P. P., Folsom, A. R. & Chambless, L. E. Heart failure incidence and survival (from the Atherosclerosis risk in communities study). Am. J. Cardiol. 101, 1016–1022 (2008).
  2. Planelles-Herrero, V.J., Hartman, J.J., Robert-Paganin, J., Malik, F.I. & Houdusse, A. Mechanistic and structural basis for activation of cardiac myosin force production by Omecamtiv mecarbil. Nat Comm. In press.
  3. Sirigu, S., Hartman, J.J., Planelles-Herrero, V.J., Ropars, V., Clancy, S., Wang, X., Chuang, G., Qian, X., Pu-Ping, L., Barrett, E., Rudolph, K., Royer, C., Morgan, B.P., Stura, E.A., Malik. F.I. & Houdusse, A. Highly selective inhibition of myosin motors provides the basis of potential therapeutic application. Proc. Natl Acad. Sci. USA 113, E7448–E7455 (2016).