<i>In Vitro</i> and <i>In Vivo</i> Characterization of Potent Antileishmanial Methionine Aminopeptidase 1 Inhibitors

Abstract

<i>Leishmania major</i> is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of <i>L. major</i> (MetAP1_Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The <i>in vitro</i> antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with <i>L. major</i> amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic <i>L. major</i> promastigotes overexpressing MetAP1_Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the <i>in vivo</i> activities of OJT006, OJT007, and OJT008 were investigated in <i>L. major</i>-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by <i>L. major</i> infection.