Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

MELISA SAYÉ; CHANTAL REIGADA; EDWARD A. VALERA VERA; CLAUDIO A. PEREIRA; LUCRECIA GAUNA; MARIANA R. MIRANDA

PLOS NEGLECTED TROPICAL DISEASES

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2020 vol. 14

1935-2735

Chagas disease, caused by the parasite Trypanosoma cruzi, affects 7 million people worldwide. Despite there are two drugs available since 50 years ago, the therapy presents severe side effects and is not effective in the chronic phase of the disease when most of the patients are diagnosed. Crystal violet (CV) was utilized as additive in blood banks to prevent transfusion-transmitted Chagas disease. Proline is involved in many pathways, like infection establishment and life cycle progression. In this work we first demonstrate that CV has the proline permease TcAAAP069 as one of its molecular targets. Then we search in a database of already-approved drugs for compounds that were structurally related to CV under the premise ?similar structure, similar activity?. We identified three drugs that inhibit proline transport and present at least the same trypanocidal effect than benznidazole, the current treatment for Chagas disease. Finally we observed a synergistic effect with the multidrug combined treatment. Drug discovery is an expensive and time-consuming process and Chagas disease is associated with poverty. The discovery of new indications to old drugs, called drug repurposing, can facilitate a rapid and more profitable therapy application since preclinical trials and pharmacokinetic studies are already available.