Identification and Characterization of Genes Involved inLeishmaniaPathogenesis: The Potential for Drug Target Selection

Robert Duncan,Ines Lakhal-Naouar,Sreenivas Gannavaram,Hira L Nakhasi,Alain Debrabant,Ranadhir Dey

doi:10.4061/2011/428486

Robert Duncan, Ines Lakhal-Naouar + Show 4 more

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https://doi.org/10.4061/2011/428486

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Abstract

Identifying and characterizing Leishmania donovani genes and the proteins they encode for their role in pathogenesis can reveal the value of this approach for finding new drug targets. Effective drug targets are likely to be proteins differentially expressed or required in the amastigote life cycle stage found in the patient. Several examples and their potential for chemotherapeutic disruption are presented. A pathway nearly ubiquitous in living cells targeted by anticancer drugs, the ubiquitin system, is examined. New findings in ubiquitin and ubiquitin-like modifiers in Leishmania show how disruption of those pathways could point to additional drug targets. The programmed cell death pathway, now recognized among protozoan parasites, is reviewed for some of its components and evidence that suggests they could be targeted for antiparasitic drug therapy. Finally, the endoplasmic reticulum quality control system is involved in secretion of many virulence factors. How disruptions in this pathway reduce virulence as evidence for potential drug targets is presented.

Highlights

Leishmania is the causative agent of leishmaniasis, a spectrum of diseases affecting more than 12 million people worldwide
This paper focuses on our efforts to identify and characterize Leishmania donovani genes and the proteins they encode for their role in pathogenesis
In our efforts to identify genes that are differentially expressed in the virulent amastigote stage of the parasite, we identified a Leishmania homologue of the mammalian argininosuccinate synthase (ASS) gene first identified in a screen for genes altered in expression when amastigote cells undergo mitotic arrest

Summary

Introduction

Leishmania is the causative agent of leishmaniasis, a spectrum of diseases affecting more than 12 million people worldwide. From the investigation so far, this protein is essential in the amastigote stage, is demonstrated to be in a critical biochemical pathway that is already known to be an effective drug target, and is a unique parasite protein suggesting specific inhibitors will not affect mammalian COX activity. The criterion that ASS should be an essential activity has not been fully demonstrated More characterization such as the demonstration that ASS is essential for survival as an amastigote and the description of subsequent steps in its metabolic pathway since the parasite does not have the enzymes to convert argininosuccinate to arginine will be needed; the increased expression in the amastigote stage, the important biochemical pathway, the existence of specific inhibitors, and the divergence in subcellular localization between the mammalian enzyme and the Leishmania enzyme indicate a potential for ASS as a target of therapeutic drugs to treat leishmaniasis

The Ubiquitin Conjugation System as Target for Chemotherapy

Findings

Conclusion