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

ACS Infect Dis. 2020 Mar 13;6(3):515-528. doi: 10.1021/acsinfecdis.9b00426. Epub 2020 Jan 30.

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.

Keywords: Leishmania donovani; Trypanosoma cruzi; cytochrome b; drug target; mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiparasitic Agents / chemistry
  • Antiparasitic Agents / isolation & purification
  • Antiparasitic Agents / pharmacology*
  • Chagas Disease / drug therapy
  • Cytochromes b / antagonists & inhibitors*
  • Cytochromes b / genetics
  • Drug Discovery*
  • High-Throughput Screening Assays
  • Humans
  • Leishmania donovani / drug effects*
  • Leishmania donovani / genetics*
  • Leishmaniasis, Visceral / drug therapy
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / genetics*

Substances

  • Antiparasitic Agents
  • Cytochromes b