Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.

Autor: Reader J; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa., van der Watt ME; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa., Taylor D; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa., Le Manach C; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa., Mittal N; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093-076, USA., Ottilie S; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093-076, USA., Theron A; Next Generation Health, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa., Moyo P; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa., Erlank E; Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa., Nardini L; Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa., Venter N; Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa., Lauterbach S; Department of Molecular Medicine and Hematology, Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa., Bezuidenhout B; Department of Molecular Medicine and Hematology, Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa., Horatscheck A; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa., van Heerden A; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa., Spillman NJ; Division of Infectious Diseases, Department of Medicine, Washington University, St. Louis, MO, 63110, USA., Cowell AN; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093-076, USA., Connacher J; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa., Opperman D; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa., Orchard LM; Department of Biochemistry & Molecular Biology and the Huck Centre for Malaria Research, Pennsylvania State University, University Park, PA, 16802, USA., Llinás M; Department of Biochemistry & Molecular Biology and the Huck Centre for Malaria Research, Pennsylvania State University, University Park, PA, 16802, USA.; Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA., Istvan ES; Division of Infectious Diseases, Department of Medicine, Washington University, St. Louis, MO, 63110, USA., Goldberg DE; Division of Infectious Diseases, Department of Medicine, Washington University, St. Louis, MO, 63110, USA., Boyle GA; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa., Calvo D; Global Health Incubator Unit, GlaxoSmithKline (GSK), Severo Ochoa, 2, 28760, Tres Cantos, Madrid, Spain., Mancama D; Next Generation Health, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa., Coetzer TL; Department of Molecular Medicine and Hematology, Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa., Winzeler EA; Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093-076, USA., Duffy J; Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215, Geneva, Switzerland., Koekemoer LL; Wits Research Institute for Malaria, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2193, South Africa., Basarab G; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa., Chibale K; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, Cape Town, 7701, South Africa.; South African Medical Research Council, Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa., Birkholtz LM; Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Hatfield, Pretoria, 0028, South Africa. lbirkholtz@up.ac.za.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jan 11; Vol. 12 (1), pp. 269. Date of Electronic Publication: 2021 Jan 11.
DOI: 10.1038/s41467-020-20629-8
Abstrakt: Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H + -ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.
Databáze: MEDLINE