Application of Computer-Guided Drug Repurposing to the Discovery of New Potential Treatments for Infectious Diseases

ALAN TALEVI; MARÍA L. SBARAGLINI; CAROLINA L. BELLERA; CATALINA ALBA SOTO; CAROLINA CARRILLO

Encuentro; Infectious Diseases Virtual 2020; 2020

Magnus Group

drug repurposing consists in finding and developing new therapeutic indications for existing drugs (i.e. approved, discontinued, shelved or experimental drugs at clinical trials). Since the new indications are built on previouspharmacokinetic and safety knowledge, this strategy can expedite the development of innovative medications and it can also serve to rescue failed drug candidates Whereas the first drug repurposing examples originated in serendipitous / nonorganized discoveries, the drug discovery community currently explores repurposing prospects in a systematic manner, frequently relying on bioinformatic and cheminformatic approaches. Here, we will discuss the application of computer-guided drug repositioning to identify potential new treatments for Chagas disease, an infectious parasitic disease historically endemic to Latin America, caused by the infectious agent Trypanosomacruzi. Using a combination of ligand- and structure-based approaches, the antibiotic clofazimine and the antihypertensive agent benidipinewere selected as promising anti-chagasic compounds. The computational predictions were validatedexperimentally, confirming the trypanocidal effects of both drugs, alone and in combination with benznidazole, both in vitro and in vivo (including an acute and a chronic model of Chagas disease). Both candidates showed trypanocidal effects against Trypanosoma cruziepimastigotes and amastigotes were able to reduceparasitemia in an acute model of Chagas disease. In the chronic model, benidipine and clofazimine were able to reduce the parasite burden in cardiac and skeletal muscles of chronically infected mice compared with untreated mice as well as diminish the inflammatory process in these tissues.We found that both drugs appear to actadditively and synergistically in combination with benznidazole.