The Qi Site of Cytochrome b is a Promiscuous Drug Target in Trypanosoma cruzi and Leishmania donovani.

Richard J Wall,Sandra Carvalho,Juan Cantizani-Perez,Susan Wyllie,Lalitha Sastry,Juan A Bueren-Calabuig,Lorna Maclean,Rachel Milne,Fabio Zuccotto,Timothy J Miles,Stephen Thompson,Sujatha Manthri,Albane Kessler,Manu De Rycker,Alan H Fairlamb,Ignacio Cotillo,Stephen Patterson,Michael G Thomas,Ian H Gilbert,Sónia Moniz ,María Marco ,Julio Martín

doi:10.1021/acsinfecdis.9b00426

Abstract

Available treatments for Chagas’ disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics. Drug discovery efforts for both diseases principally rely upon phenotypic screening. However, the optimization of phenotypically active compounds is hindered by a lack of information regarding their molecular target(s). To combat this issue we initiate target deconvolution studies at an early stage. Here, we describe comprehensive genetic and biochemical studies to determine the targets of three unrelated phenotypically active compounds. All three structurally diverse compounds target the Qi active-site of cytochrome b, part of the cytochrome bc1 complex of the electron transport chain. Our studies go on to identify the Qi site as a promiscuous drug target in Leishmania donovani and Trypanosoma cruzi with a propensity to rapidly mutate. Strategies to rapidly identify compounds acting via this mechanism are discussed to ensure that drug discovery portfolios are not overwhelmed with inhibitors of a single target.

Highlights

Available treatments for Chagas’ disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics
High-throughput screening of GSK’s 1.8 M diverse compound library against L. donovani, T. cruzi, and Trypanosoma brucei resulted in the identification of a significant number of compounds active against these parasites.[13]
In the absence of robustly validated molecular targets to support target-based studies, large-scale phenotypic screens have been used to identify start points for drug discovery. This approach allows the efficient identification of parasite growth inhibitors and has the potential to identify new and exploitable molecular targets when coupled to drug target deconvolution studies

Summary

Introduction

Available treatments for Chagas’ disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics. Among the “most neglected” NTDs are Chagas’ disease (CD) infecting 7−8 million in Central and South America and visceral leishmaniasis (VL), with up to 100 000 new cases arising each year predominantly in rural India, Sudan, South Sudan, Kenya, Somalia, Ethiopia, and Brazil Combined, these diseases are responsible for more than 40 000 fatalities annually and the loss of over 1.2 million disease adjusted life years.[1,2] The accompanying economic burden of these vector-borne diseases provides a major obstacle to improving human health.[3] Current treatments for both VL and CD suffer from a range of issues including severe toxic side effects[4,5] and acquired drug resistance.[6] To compound these difficulties, many of these chemotherapeutics require prolonged treatment regimens[7] and are prohibitively expensive. A more complete understanding of the compound mechanism of action (MoA) can prevent enrichment of drug candidates against the same molecular target or the development of inhibitors with an unattractive or invalidated target, such as sterol 14α-demethylase (CYP51) in T. cruzi.[11,12]

Methods

Results

Conclusion