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Open-source discovery of chemical leads for next-generation chemoprotective antimalarials.
Antonova-Koch, Yevgeniya; Meister, Stephan; Abraham, Matthew; Luth, Madeline R; Ottilie, Sabine; Lukens, Amanda K; Sakata-Kato, Tomoyo; Vanaerschot, Manu; Owen, Edward; Jado, Juan Carlos; Maher, Steven P; Calla, Jaeson; Plouffe, David; Zhong, Yang; Chen, Kaisheng; Chaumeau, Victor; Conway, Amy J; McNamara, Case W; Ibanez, Maureen; Gagaring, Kerstin; Serrano, Fernando Neria; Eribez, Korina; Taggard, Cullin McLean; Cheung, Andrea L; Lincoln, Christie; Ambachew, Biniam; Rouillier, Melanie; Siegel, Dionicio; Nosten, François; Kyle, Dennis E; Gamo, Francisco-Javier; Zhou, Yingyao; Llinás, Manuel; Fidock, David A; Wirth, Dyann F; Burrows, Jeremy; Campo, Brice; Winzeler, Elizabeth A.
Afiliação
  • 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.
  • Sakata-Kato T; The Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
  • Vanaerschot M; The Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
  • Owen E; Division of Infectious Diseases, Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
  • Jado JC; Department of Biochemistry and Molecular Biology and Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA.
  • Maher SP; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Calla J; Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.
  • Plouffe D; Department of Global Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL 33612, USA.
  • Zhong Y; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Chen K; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
  • Chaumeau V; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
  • Conway AJ; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
  • McNamara CW; Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
  • Ibanez M; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Gagaring K; Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.
  • Serrano FN; Department of Global Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL 33612, USA.
  • Eribez K; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
  • Taggard CM; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
  • Cheung AL; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
  • Lincoln C; Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain.
  • Ambachew B; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Rouillier M; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Siegel D; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Nosten F; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Kyle DE; School of Medicine, University of California, San Diego, 9500 Gilman Drive 0760, La Jolla, CA 92093, USA.
  • Gamo FJ; Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland.
  • Zhou Y; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive 0741, La Jolla, CA 92093, USA.
  • Llinás M; Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
  • Fidock DA; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Wirth DF; Center for Tropical and Emerging Global Diseases, University of Georgia, 500 D. W. Brooks Drive, Athens, GA 30602, USA.
  • Burrows J; Department of Global Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL 33612, USA.
  • Campo B; Medicines for Malaria Venture, Post Office Box 1826, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland.
  • Winzeler EA; The Genomics Institute of the Novartis Research Foundation, 10675 John J Hopkins Drive, San Diego, CA 92121, USA.
Science ; 362(6419)2018 12 07.
Article em En | MEDLINE | ID: mdl-30523084
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmodium / Quimioprevenção / Descoberta de Drogas / Malária / Antimaláricos Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmodium / Quimioprevenção / Descoberta de Drogas / Malária / Antimaláricos Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article