The Q_i Site of Cytochrome <i>b</i> is a Promiscuous Drug Target in <i>Trypanosoma cruzi</i> and <i>Leishmania donovani</i>

Journal article

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

Authors: Wall, RJ; Carvalho, S; Milne, R; Bueren-Calabuig, JA; Moniz, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: ACS Infectious Diseases
• Volume: 6
• Issue: 3
• Pages: 515-528
• Publication date: 2020-01-22
• DOI: 10.1021/acsinfecdis.9b00426
• EISSN: 2373-8227
• ISSN: 2373-8227
• Language: English
• Keywords: Leishmania; Computer science; Trypanosoma cruzi; Drug; Chagas disease; Immunology; Antiparasitic agent; Biology; Parasite hosting; Pharmacology; Leishmania donovani; Microbiology; Virology; Leishmaniasis; Visceral leishmaniasis; Trypanosoma