In vitro and in vivo characterization of potent antileishmanial methionine aminopeptidase 1 inhibitors

Felipe Rodriguez, Sarah F. John, Eva Iniguez, Sebastian Montalvo, Karina Michael, Lyndsey White, Dong Liang, Omonike A. Olaleye, Rosa A. Maldonado

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Leishmania major 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 L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro 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 L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-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 L. major infection.

Original languageEnglish (US)
Article numbere01422-19
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Antiparasitic agents
  • Cutaneous leishmaniasis
  • Drug discovery
  • Leishmania major
  • Methionine aminopeptidase 1
  • Molecular parasitology
  • Murine model of cutaneous leishmaniasis
  • Parasitology
  • Target validation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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