Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure

Changwon Kho, Ahyoung Lee, Dongtak Jeong, Jae Gyun Oh, Przemek A. Gorski, Kenneth Fish, Roberto Sanchez, Robert J. DeVita, Geir Christensen, Russell Dahl and Roger J. Hajjar ()
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Changwon Kho: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Ahyoung Lee: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Dongtak Jeong: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Jae Gyun Oh: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Przemek A. Gorski: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Kenneth Fish: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai
Roberto Sanchez: Icahn School of Medicine at Mount Sinai
Robert J. DeVita: Icahn School of Medicine at Mount Sinai
Geir Christensen: Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo
Russell Dahl: Rosalind Franklin University of Medicine and Science
Roger J. Hajjar: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8229

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