Changwon Kho1,†, Ahyoung Lee1,†, Dongtak Jeong1, Jae Gyun Oh1, Przemek A. Gorski1, Kenneth Fish1, Roberto Sanchez2, Robert J. DeVita2,3, Geir Christensen4, Russell Dahl5 & Roger J. Hajjar1
1 Department of Medicine/Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy place, Box 1030, New York, New York 10029, USA. 2 Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 3 Department of Pharmacology and System Therapeutics, Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 4 Institute for Experimental Medical Research, Oslo University Hospital Ulleval and University of Oslo, Oslo 0450, Norway. 5 Department of Pharmaceutical Science, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA. †These authors contributed equally to this work.
Correspondence to : Roger J. Hajjar
Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a and have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function. Here, we identify and characterize a small molecule, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. We identify a pocket on SUMO E1 likely to be responsible for N106’s effect. N106 treatment increases contractile properties of cultured rat cardiomyocytes and significantly improves ventricular function in mice with heart failure. This first-in-class small-molecule activator targeting SERCA2a SUMOylation may serve as a potential therapeutic strategy for treatment of heart failure.