Computer-guided drug repurposing: Identification of clofazimine as a treatment for Chagas disease.

CATALINA ALBA SOTO; CAROLINA CARRILLO; RICARDO J. GELPI; CRISTIAN MIRANDA; JAZMÍN KELLY; YÉSICA ARECO; CAROLINA L. BELLERA; ALAN TALEVI; PATRICIA ROMANO; BRUNO BUCHHOLZ; MARÍA L. SBARAGLINI

CABA

Congreso; Drug Discovery for Neglected Diseases International Congress 2018 4th Scientific Meeting of ResNet NPND; 2018

Introduction. 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.Objective. 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.Materials and methods. 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 [3, 4], confirming trypanocidal effects 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 combined clofazimine + benznidazole therapy using a low dose benznidazole (30mg/kg/d) in a murine model of chronic infection.Results. Clofazimine (as monotherapy) showed a reduction in quantitative and qualitative parameters of inflammation in skeletal muscle compared with untreated mice. Treatment with clofazimine alone did not achieve sterile cure. Combined therapy reduced parasitic load in peripheral blood whereas a non-significant trend to reduce parasite burden was observed in striated muscles. Histopathological studies showed a beneficial effect of combined therapy over benznidazole 75 mg/kg/day regarding muscle fiber damage. Combined therapy showed no significant differences in heart rate, length of RR, QT and RP intervals between groups.Discussion. The results reveal the clofazimine?s ability to reduce the parasite load in acute and chronic murine models of 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 conventional treatments and to enhance the beneficial effect of monotherapy.Conclusion. With the help of computational tools we found a new trypanocidal compound with potential against American trypanosomiasis, with a minimal investment of time and resources, which showed beneficial effects on different models of infection, both as monotherapy and as combined therapy with benznidazole.