Drug repositioning to identify drugs that ameliorate cytokine-induced mitochondrial dysfunction in cardiomyocytes: Validation of hits found after screening of drug library

• Grant number: 23/18345-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2024
• End date: May 31, 2027
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Edecio Cunha Neto
• Grantee: Vinicius Moraes de Paiva Roda
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 22/00758-0 - Mitochondria, interferon-gamma and genetics in Chagas Disease cardiomyopathy: pathogenesis, therapeutic targets and prognostic markers, AP.TEM

Abstract

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, affects around 6 million people, with no effective antiparasitic medications or vaccines. About 30% of CD patients develop chronic Chagasic cardiomyopathy (CCC), an inflammatory myocardial disease that occurs decades after infection. Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are implicated in the onset of arrhythmias and triggering events. Survival in CCC is worse than in other cardiomyopathies, reflecting limited knowledge about its pathogenesis. Recent findings from our group and others, derived from analyses of CCC patients and in vitro studies with cardiomyocytes, point to cytokine-induced mitochondrial dysfunction, such as IFN-³ and TNF-±, as a potential mechanism involved in CCC pathogenesis. Collectively, these studies have shown that downstream signaling of IFN-³ and TNF-± causing mitochondrial dysfunction in cardiomyocytes is a potential therapeutic target. In this project, we aim to screen compounds already used in humans as therapy for other diseases, repurposing drugs in the cytokine signaling causing mitochondrial dysfunction in in vitro cultured cardiomyocytes, followed by in vivo validation of active drugs in a murine model of IFN-³-dependent inflammatory dilated cardiomyopathy. Drug repurposing is an interesting strategy for neglected diseases like Chagas disease because it saves time and reduces costs associated with developing a new pharmacological agent.