3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR) Enzyme of the Sterol Biosynthetic Pathway: A Potential Target against Visceral Leishmaniasis

Abstract

Sterol biosynthetic pathway is explored for its therapeutic potential for Visceral Leish­ maniasis. In Leishmania , this pathway produces ergosterol which is absent in host and there­ fore is a promising strategy to combat proliferation of both extracellular and intracellular forms of the parasite with minimal host toxicity. The present chapter focuses on 3­hydroxy­ 3­methylglutaryl­CoA reductase (HMGR) enzyme which is the rate­limiting enzyme of the ergosterol biosynthesis. HMGR gene of L. donovani was biochemically and biophysically characterized for the first time. HMGR over expressing transgenic parasites were generated to evaluate its role in parasite growth and infection ability. A series of statins like atorvas ­ tatin, simvastatin and mevastatin were evaluated for its therapeutic efficacy and mode of action elucidated. Atorvastatin and mevastatin were found to be killing both the promas ­ tigote and amastigote forms of the parasite without exhibiting host cytotoxicity. Besides, non-statin class of molecules like resveratrol and glycyrrhizic acid were also analyzed for antileishmanial potential. Two antidepressants, ketanserin and mianserin were found to kill both L. donovani promastigotes and intracellular amastigotes with no apparent toxicity to the host cells. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present work may have implications in treatment of Leishmaniasis. The present review encompasses functional characterization of L. donovani HMGR enzyme and the evaluation of the effect of various HMGR inhibitors as potential candidates for treat ­ ment of Leishmaniasis. Inhibitors which showed inhibition of both the extracellular and intra­ cellular forms of the parasites at low micromolar range with no cytotoxicity to host cells are promising antileishmanial candidates. They can be further explored in an experimental ani­ mal model of VL to evaluate its anti-VL efficacy.