Synthesis and characterization of quinoline-carbaldehyde derivatives as novel inhibitors for leishmanial methionine aminopeptidase 1

Abstract

Methionine aminopeptidase 1 of Leishmania donovani (LdMetAP1) is a novel antileishmanial target for its role in vital N-terminal methionine processing. After LdMetAP1 expression and purification, we employed a series of biochemical assays to determine optimal conditions for catalysis, metal dependence and substrate preferences for this ubiquitous enzyme. Screening of newly synthesized quinoline-carbaldehyde derivatives in inhibition assays led to the identification of HQ14 and HQ15 as novel and specific inhibitors for LdMetAP1 which compete with substrate for binding to the catalytic active site. Both leads bind LdMetAP1 with high affinity and possess druglikeness. Biochemical studies suggested HQ14 and HQ15 to be comparatively less effective against purified HsMetAP1 and showed no or less toxicity. We further show selectivity and inhibition of lead inhibitors is sensed through a non-catalytic Thr residue unique to LdMetAP1. Finally, structural studies highlight key differences in the binding modes of HQ14 and HQ15 to LdMetAP1 and HsMetAP1 providing structural basis for differences in inhibition. The study demonstrates the feasibility of deploying small drug like molecules to selectively target the catalytic activity of LdMetAP1 which may provide an effective treatment of leishmaniasis.