Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.

Autor: Antonova-Koch Y; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Meister S; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Abraham M; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Luth MR; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Ottilie S; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Lukens AK; Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.; The Broad Institute, 415 Main Street, Cambridge, MA 02142, USA., Sakata-Kato T; The Broad Institute, 415 Main Street, Cambridge, MA 02142, USA., Vanaerschot M; Division of Infectious Diseases, Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA., Owen E; Department of Biochemistry and Molecular Biology and Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA., Jado JC; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Maher SP; Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.; Department of Global Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL 33612, USA., Calla J; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Plouffe D; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Zhong Y; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Chen K; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Chaumeau V; Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Conway AJ; Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.; Department of Global Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL 33612, USA., McNamara CW; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Ibanez M; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Gagaring K; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Serrano FN; Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain., Eribez K; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Taggard CM; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Cheung AL; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Lincoln C; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Ambachew B; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA., Rouillier M; Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland., Siegel D; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive 0741, La Jolla, CA 92093, USA., Nosten F; Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Kyle DE; Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.; Department of Global Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL 33612, USA., Gamo FJ; Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland., Zhou Y; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA., Llinás M; Department of Biochemistry and Molecular Biology and Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA.; Department of Chemistry and Center for Infectious Diseases Dynamics, Pennsylvania State University, University Park, PA 16802, USA., Fidock DA; Division of Infectious Diseases, Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA., Wirth DF; Harvard T. H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.; The Broad Institute, 415 Main Street, Cambridge, MA 02142, USA., Burrows J; Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland., Campo B; Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland., Winzeler EA; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA. ewinzeler@ucsd.edu.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive 0741, La Jolla, CA 92093, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2018 Dec 07; Vol. 362 (6419).
DOI: 10.1126/science.aat9446
Abstrakt: To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.
(Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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