Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Autor: de Vries LE; Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Jansen PAM; Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Barcelo C; Medicines for Malaria Venture, Geneva, Switzerland., Munro J; Department of Chemistry and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA, USA., Verhoef JMJ; Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Pasaje CFA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Rubiano K; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA., Striepen J; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA., Abla N; Medicines for Malaria Venture, Geneva, Switzerland., Berning L; TropIQ Health Sciences, Nijmegen, The Netherlands., Bolscher JM; TropIQ Health Sciences, Nijmegen, The Netherlands., Demarta-Gatsi C; Medicines for Malaria Venture, Geneva, Switzerland., Henderson RWM; TropIQ Health Sciences, Nijmegen, The Netherlands., Huijs T; TropIQ Health Sciences, Nijmegen, The Netherlands., Koolen KMJ; TropIQ Health Sciences, Nijmegen, The Netherlands., Tumwebaze PK; Infectious Diseases Research Collaboration, Kampala, Uganda., Yeo T; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA., Aguiar ACC; Sao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil, São Carlos, SP, Brazil., Angulo-Barturen I; The Art of Discovery, Derio, Spain., Churchyard A; Department of Life Sciences, Imperial College London, South Kensington, London, United Kingdom., Baum J; Department of Life Sciences, Imperial College London, South Kensington, London, United Kingdom., Fernández BC; Global Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain., Fuchs A; Medicines for Malaria Venture, Geneva, Switzerland., Gamo FJ; Global Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain., Guido RVC; Sao Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo, Brazil, São Carlos, SP, Brazil., Jiménez-Diaz MB; The Art of Discovery, Derio, Spain., Pereira DB; Research Center for Tropical Medicine of Rondonia, Porto Velho, Brazil., Rochford R; Department of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA., Roesch C; Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.; Malaria Translational Research Unit, Institut Pasteur, Paris & Institut Pasteur du Cambodge, Phnom Penh, Cambodia., Sanz LM; Global Health, GlaxoSmithKline, Tres Cantos, Madrid, Spain., Trevitt G; Sygnature Discovery, Nottingham, United Kingdom., Witkowski B; Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.; Malaria Translational Research Unit, Institut Pasteur, Paris & Institut Pasteur du Cambodge, Phnom Penh, Cambodia., Wittlin S; Swiss Tropical and Public Health Institute, Basel, Switzerland.; University of Basel, Basel, Switzerland., Cooper RA; Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, USA., Rosenthal PJ; Department of Medicine, University of California, San Francisco, CA, USA., Sauerwein RW; Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; TropIQ Health Sciences, Nijmegen, The Netherlands., Schalkwijk J; Department of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Hermkens PHH; Hermkens Pharma Consultancy, Oss, The Netherlands., Bonnert RV; Medicines for Malaria Venture, Geneva, Switzerland., Campo B; Medicines for Malaria Venture, Geneva, Switzerland., Fidock DA; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA., Llinás M; Department of Chemistry and Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA, USA.; Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, USA., Niles JC; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Kooij TWA; Department of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. taco.kooij@radboudumc.nl., Dechering KJ; TropIQ Health Sciences, Nijmegen, The Netherlands. k.dechering@tropiq.nl.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 20; Vol. 13 (1), pp. 2158. Date of Electronic Publication: 2022 Apr 20.
DOI: 10.1038/s41467-022-29688-5
Abstrakt: Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.
(© 2022. The Author(s).)
Databáze: MEDLINE
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