Abstract
Heart failure is a leading cause of death worldwide, and even with current treatments, the 5-y transplant-free survival rate is only ~50 to 70%. As such, there is a need to develop new treatments for patients that improve survival and quality of life. Recently, there have been efforts to develop small molecules for heart failure that directly target components of the sarcomere, including cardiac myosin. Danicamtiv is one of these molecules; however, its direct effects on myosin’s single molecule mechanics and kinetics are not well understood. Using optical trapping techniques, stopped flow transient kinetics, and in vitro reconstitution assays, we found that danicamtiv reduces the size of cardiac myosin’s working stroke without affecting actomyosin detachment kinetics at the level of individual crossbridges. We demonstrate that danicamtiv accelerates actomyosin association kinetics, leading to increased recruitment of myosin crossbridges and subsequent thin filament activation at physiologically relevant calcium concentrations. We demonstrate important mechanistic differences with another cardiac myosin binding myotrope, omecamtiv mecarbil. Finally, we computationally model how the observed changes in mechanics and kinetics at the level of single crossbridges can contribute to increased cardiac contraction. Taken together, our results have important implications for the design of sarcomeric-targeting compounds for heart failure.
| Original language | English |
|---|---|
| Article number | e2515786122 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 122 |
| Issue number | 34 |
| DOIs | |
| State | Published - Aug 26 2025 |
Bibliographical note
Publisher Copyright:Copyright © 2025 the Author(s).
Funding
We acknowledge financial support provided by the NIH (R01 HL141086 and R01 HL174866 to M.J.G., R01 HL148785 to K.S.C., T32 HL125241 to B.S.), the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (PM-LI-2019-829 M.J.G.), and the American Heart Association (TPA 970198 to M.J.G., 23TPA1074093 to K.S.C.). ACKNOWLEDGMENTS. We acknowledge financial support provided by the NIH (R01 HL141086 and R01 HL174866 to M.J.G., R01 HL148785 to K.S.C., T32 HL125241 to B.S.), the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (PM-LI-2019-829 M.J.G.), and the American Heart Association (TPA 970198 to M.J.G., 23TPA1074093 to K.S.C.).
| Funders | Funder number |
|---|---|
| Children's Discovery Institute | |
| National Institutes of Health (NIH) | R01 HL141086, R01 HL148785, T32 HL125241, R01 HL174866 |
| St. Louis Children's Hospital | PM-LI-2019-829 |
| American the American Heart Association | TPA 970198, 23TPA1074093 |
Keywords
- cardiac myosin
- contractility
- single molecule
ASJC Scopus subject areas
- General