Modulating HSP90 Interactome As A Potential Therapeutic Target in Cardiac Disease

• Haaris Madaha, Medical Diagnostics, University of Delaware

• Chi Keung Lam, Biological Sciences, University of Delaware

Cardiac disease is one of the leading causes of death worldwide. Existing therapies have failed to effectively address the issue due to the complicated etiology of heart diseases, caused by the simultaneous occurrence of different molecular and cellular dysfunctions. This creates an urgent need for a therapeutic target that can correct several of these dysfunctions at the same time. Heat shock protein 90 (HSP90) is known to participate in the proteostasis of proteins involved in key cardiac signaling Pathways Previous studies have established that HSP90 interacts with HCLS1-associated protein X-1 (HAX-1) to inhibit the activity of sarco-endoplasmic reticulum Ca 2+ ATPase (SERCA) pump and cardiac contractility. As compromised contractility, SERCA function and reduced cardiomyocyte survival are observed in most cases of heart disease, our overall goal is to design cell-permeable interfering peptides to modulate the HSP90/HAX-1 binding to improve contractility and cardiomyocyte survival under stress. We have used binding assays to determine the interacting domains of HSP90 and HAX-1 on each other for the design of the interfering peptides. The Antennapedia peptide sequence has been added to these domains to make the interfering peptides cell permeable. Our preliminary data on contractility studies in human-induced pluripotent stem cells (hiPScs) have indicated improved contractility upon interfering peptide treatment. Future studies are directed to examine cardioprotective effects of the interfering peptides.