Computer guided drug repurposing: identification of clofazimine as a treatment for Chagas disease

BELLERA CL; SBARAGLINI ML; ARECO Y; MIRANDA C; BUCHHOLZ B; KELLY J; GELPI R; ROMANO PS; CARRILLO C; ALBA SOTO CD; TALEVI A

CABA

Congreso; Drug Discovery for Neglected Diseases International Congress 2018 4th Scientific Meeting of the Research Network Natural Products against Neglected Diseases; 2018

DDNDIC

Only two drugs are currently used to treat Chagas disease, namely, benznidazole and nifurtimox. Both require long treatments, display severe side effects and have controversial efficacy in chronically T. cruzi-infected adults [1,2].Therefore, we need safe and efficacious treatment alternatives against Chagas disease. Building ligand-based in silico models capable of identifying novel Cruzipain inhibitors, for subsequent evaluation of the selected drugs in experiments in vitro and in vivo.Using an in silico strategy focused on drug repurposing, clofazimine, an antibiotic indicated for the treatment of leprosy, emerged as an interesting candidate for the treatment of Chagas disease, as previously reported [3,4]. Its trypanocidal effect were confirmed against the replicative forms of T. cruzi. Later, a murine model of acute Chagas infection was implemented where clofazimine reduced the number of parasites in peripheral blood and the number of amastigote nests in cardiac tissue. Thus, we studied the effects of clofazimine alone and in combination with benznidazole, using a low dose of benznidazole (30 mg/kg/d) in a murine model of chronic infection (RA strain). Benznidazole 75 mg/kg/d and non-treated animals were used as controls. Clofazimine (as monotherapy), showed a reduction in quantitative and qualitative parameters of inflammation in skeletal muscle compared with untreated mice. Though it reduced parasitemia, it did not achieve sterile cure. On the other hand, combined therapy showed a non-significant compared to the untreated group trend to reduce parasite burden in striated muscles and reduced parasitic load in peripheral blood. Combination therapy showed no significant differences in heart rate, length of RR, QT and RP intervals between groups; at the histopathological level, it showed a beneficial effect over benznidazole 75 mg/kg/day in regard to muscle fiber damage. The results reveal clofazimine?s ability to reduce the parasite load in acute and chronic murine modelsof Chagas disease, and to reduce the inflammatory effects of chronic infection in muscle. Combination treatment displayed some advantages, and it could be an alternative strategy to reduce the dose and/or duration of conventionaltreatments, possibly enhancing the beneficial effect of monotherapy. With the help of computational tools, we found a new trypanocidal compound with potential against American trypanosomiasis, with a minimal investment of time andresources, which showed beneficial effects on different models of infection, both as monotherapy and as combined therapy with benznidazole.