Squalene synthase as a target for Chagas disease therapeutics.

Na Shang,Eric Oldfield,Phercyles Veiga-Santos,Qian Li,Kai Li,Julio A Urbina,Jikun Li,Wanderley De Souza,Roberto Docampo,Yingying Zheng,Melina Galizzi,Feifei Ren,Zhu Hong Li ,H.c Chan ,Técia Maria Ulisses De Carvalho ,Dolores González-Pacanowska ,Yi Liang Liu ,Chun‐Chi Chen ,Tzu Ping Ko ,Chih-Hsien Huang ,Zhaohai Zhu ,Andrew H.j Wang ,Carlos A Rodrígues-Poveda ,Rey‐Ting Guo

doi:10.1371/journal.ppat.1004114

Abstract

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

Highlights

Many millions of individuals are infected with the so-called ‘‘World’s most neglected diseases’’
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects eight million individuals, primarily in Latin America
This parasite use a variety of sterols, rather than cholesterol in their cell membranes, so inhibiting endogenous sterol biosynthesis is an important therapeutic target

Summary

Introduction

Many millions of individuals are infected with the so-called ‘‘World’s most neglected diseases’’ These include the leishmaniases, with ,12 million individuals affected [1], and in Latin America, Chagas disease. There are no cures available for the chronic form of the disease which can involve cardiac myopathy, mega-oesophagus and mega-colon, clinical trials with the azole drug posaconazole and a ravuconazole prodrug are in progress [5,6]. Both of these compounds function by blocking the ergosterol biosynthesis pathway [7,8] shown, as described in a recent review [9] Both of these compounds function by blocking the ergosterol biosynthesis pathway [7,8] shown in Figure 1A, as described in a recent review [9]

Methods

Results

Conclusion