Roman Manetsch

Sponsor: NIH

Activation of Benzoxaborole Prodrug AN15368, a Clinical Candidate for Chagas Disease

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is endemic in the Americas, but has also globalized due to human migration. Despite being one of the major causes of infection-induced heart disease worldwide, current therapies for Chagas disease have inconsistent efficacy and frequent side effects. A major contributor to treatment failure is thought to be the transiently dormant intracellular forms of T. cruzi that are resistant to otherwise highly effective trypanocidal compounds. The newly discovered benzoxaborole AN15368 represents the first extensively validated and safe clinical candidate for the treatment of Chagas disease. AN15368 acts as a prodrug that requires cleavage by parasite serine carboxypeptidases (TcCBPs) to yield the active metabolite. This proposal aims to gain additional understanding of this processing step for AN15368 as a prodrug, as well as to assess the potential for acquired resistance as this compound proceeds toward human clinical trials.