Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Fletcher, Sabine; Lucantoni, Leonardo; Sykes, Melissa; Jones, Amy; Holleran, John; Saliba, Kevin; Avery, Vicky
• Is Part Of: Parasites & vectors. Volume 9:Issue 1(2016)
• Page Start: 1
• Page End: 13
• Publication Date: 2016-12
• Subjects: Coenzyme A synthesis -- Plasmodium falciparum -- Gametocytes -- Trypanosoma brucei brucei -- Trypanosoma cruzi -- Drug discovery; Parasitism -- Periodicals; Parasites -- Periodicals; Vector-pathogen relationships -- Periodicals; Animals as carriers of disease -- Periodicals; Insects as carriers of disease -- Periodicals; 616.96
• DOI: 10.1186/s13071-016-1860-3
• Languages: English
• ISSNs: 1756-3305

Abstract

Abstract Background In the fight against malaria, the discovery of chemical compounds with a novel mode of action and/or chemistry distinct from currently used drugs is vital to counteract the parasite's known ability to develop drug resistance. Another desirable aspect is efficacy against gametocytes, the sexual developmental stage of the parasite which enables the transmission throughAnopheles vectors. Using a chemical rescue approach, we previously identified compounds targetingPlasmodium falciparum coenzyme A (CoA) synthesis or utilization, a promising target that has not yet been exploited in anti-malarial drug development. Results We report on the outcomes of a series of biological tests that help to define the species- and stage-specificity, as well as the potential targets of these chemically diverse compounds. Compound activity againstP. falciparum gametocytes was determined to assess stage-specificity and transmission-reducing potential. Against early stage gametocytes IC50 values ranging between 60 nM and 7.5 μM were obtained. With the exception of two compounds with sub-micromolar potencies across all intra-erythrocytic stages, activity against late stage gametocytes was lower. None of the compounds were specific pantothenate kinase inhibitors. Chemical rescue profiling with CoA pathway intermediates demonstrated that most compounds acted on either of the two finalP. falciparum CoA synthesis enzymes, phosphopantetheine adenylyltransferase (PPAT) or dephospho CoA kinase (DPCK). The most active compound targeted either phosphopantothenoylcysteine synthetase (PPCS) or phosphopantothenoylcysteine decarboxylase (PPCDC). Species-specificity was evaluated againstTrypanosoma cruzi andTrypanosoma brucei brucei . No specific activity againstT. cruzi amastigotes was observed; however three compounds inhibited the viability of trypomastigotes with sub-micromolar potencies and were confirmed to act onT. b. brucei CoA synthesis. Conclusions Utilizing the compounds we previously identified as effective against asexualP. falciparum, we demonstrate for the first time that gametocytes, like the asexual stages, depend on CoA, with two compounds exhibiting sub-micromolar potencies across asexual forms and all gametocytes stages tested. Furthermore, three compounds inhibited the viability ofT. cruzi andT. b. brucei trypomastigotes with sub-micromolar potencies and were confirmed to act onT. b. brucei CoA synthesis, indicating that the CoA synthesis pathway might represent a valuable new drug target in these parasite species.