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      Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

      research-article
      1 , * , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 8 , 11 , 12 , 13 , 11 , 14 , 15 ,   16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 10 , 23 , 27 , 7 , 28 , 29 , 30 , 31 , 32 , 10 , 33 , 24 , 34 , 1 , 3 , 4 , 34 , 35 , 36 , 5 , 37 , 11 , 38 , 39 , 40 , 9 ,   41 , 22 , 25 , 42 , 43 , 44 , 45 , 42 , 46 , 31 , 47 , 20 , 47 , 14 , 48 , 49 , 50 , 51 , 52 , 53 , 35 , 54 , 38 , 3 , 4 , 49 , 31 , 55 , 32 , 2 , 56 , 3 , 4 , 45 , 57 , 58 , 59 , 19 , 2 , 43 , 60 , 51 , 14 , 59 , 60 , 45 , 58 , 28 , 26 , 61 , 11 , 62 , 63 , 64 , 21 , 20 , 65 , 49 , 37 , 23 , 66 , 25 , 67 , 14 , 45 , 68 , 50 , 8 , 1 , 23 , 45 , 13 , 11 , 12 , 1 , 60 , 3 , 4 , 69 , 34 , 61 , 11 , 43 , 70 , 11 , 2 , 8 ,   11 , 2 , 38 , 71 , 36 , 72 , 73 , 28 , 24 , 74 , 72 , 74 , 73 , 7 , 75 , 76 , 57 , 66 , 24 , 77 , 78 , 73 , 27 , 79 , 36 , 35 , 25 , 64 , 42 , 11 , 80 , 44 , 77 , 57 , 2 , 53 , 13 , 37 , 61 , 16 , 11 , 52 , 29 , 78 , 81 , 82 , 37 , 58 , 37 , 5 , 38 , 25 , 51 , 51 , 51 , 51 , 51 , 51 , 51 , 51
      PLoS Pathogens
      Public Library of Science
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          Abstract

          A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

          Author Summary

          Malaria leads to the loss of over 440,000 lives annually; accelerating research to discover new candidate drugs is a priority. Medicines for Malaria Venture (MMV) has distilled over 25,000 compounds that kill malaria parasites in vitro into a group of 400 representative compounds, called the "Malaria Box". These Malaria Box sets were distributed free-of-charge to research laboratories in 30 different countries that work on a wide variety of pathogens. Fifty-five groups compiled >290 assay results for this paper describing the many activities of the Malaria Box compounds. The collective results suggest a potential mechanism of action for over 130 compounds against malaria and illuminate the most promising compounds for further malaria drug development research. Excitingly some of these compounds also showed outstanding activity against other disease agents including fungi, bacteria, other single-cellular parasites, worms, and even human cancer cells. The results have ignited over 30 drug development programs for a variety of diseases. This open access effort was so successful that MMV has begun to distribute another set of compounds with initial activity against a wider range of infectious agents that are of public health concern, called the Pathogen Box, available now to scientific labs all over the world ( www.PathogenBox.org).

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          Most cited references61

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          Spiroindolones, a potent compound class for the treatment of malaria.

          Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.
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            Microscale culture of human liver cells for drug development.

            Tissue function depends on hierarchical structures extending from single cells ( approximately 10 microm) to functional subunits (100 microm-1 mm) that coordinate organ functions. Conventional cell culture disperses tissues into single cells while neglecting higher-order processes. The application of semiconductor-driven microtechnology in the biomedical arena now allows fabrication of microscale tissue subunits that may be functionally improved and have the advantages of miniaturization. Here we present a miniaturized, multiwell culture system for human liver cells with optimized microscale architecture that maintains phenotypic functions for several weeks. The need for such models is underscored by the high rate of pre-launch and post-market attrition of pharmaceuticals due to liver toxicity. We demonstrate utility through assessment of gene expression profiles, phase I/II metabolism, canalicular transport, secretion of liver-specific products and susceptibility to hepatotoxins. The combination of microtechnology and tissue engineering may enable development of integrated tissue models in the so-called 'human on a chip'.
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              Chemical genetics of Plasmodium falciparum

              Malaria caused by Plasmodium falciparum is a catastrophic disease worldwide (880,000 deaths yearly). Vaccine development has proved difficult and resistance has emerged for most antimalarials. In order to discover new antimalarial chemotypes, we have employed a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library, many of which exhibited potent in vitro activity against drug resistant strains, and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in multiple organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Overall, our findings provide the scientific community with new starting points for malaria drug discovery.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                28 July 2016
                July 2016
                : 12
                : 7
                : e1005763
                Affiliations
                [1 ]Departments of Medicine, Microbiology, and Global Health, Center for Emerging and Re-emerging Infectious Diseases (CERID) University of Washington, Seattle, Washington, United States of America
                [2 ]Center for Global Health and Infectious Diseases Research, Department of Global Health, University of South Florida, Tampa, Florida, United States of America
                [3 ]Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland
                [4 ]University of Basel, Basel, Switzerland
                [5 ]Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of California, San Francisco, California, United States of America
                [6 ]Departments of Physiology & Biophysics, Neuroscience and Medicine, Albert Einstein College of Medicine, New York, New York, United States of America
                [7 ]Dipartimento Malattie Infettive, Parassitarie ed Immunomediate Istituto Superiore di Sanità, Roma, Italia
                [8 ]BBD BioPhenix SL–BIOBIDE, Donostia, Gipuzkoa, Spain
                [9 ]Bigelow Laboratory for Ocean Sciences, East Boothbay, Maine, United States of America
                [10 ]Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
                [11 ]Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia
                [12 ]QIMR Berghofer Medical Research Institute Herston, Brisbane, Australia
                [13 ]School of Life Sciences, University of Nottingham, Nottingham, Nottinghamshire, England, United Kingdom
                [14 ]Institut Pasteur Korea, Pangyo Techno-Valley, Gyeonggi Province, Korea
                [15 ]Clinical Pharmacology, Novartis Consumer Health, Nyon, Switzerland
                [16 ]Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
                [17 ]Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford, England, United Kingdom
                [18 ]The London School of Hygiene and Tropical Medicine, London, England, United Kingdom
                [19 ]Internal Medicine, Yale University, New Haven, Connecticut, United States of America
                [20 ]Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
                [21 ]Department of Immunology & Infection, London School of Hygiene and Tropical Medicine, London, England, United Kingdom
                [22 ]Museum of National History, Sorbonne Universities, Paris, France
                [23 ]SCYNEXIS, Inc., Durham, North Carolina, United States of America
                [24 ]Department of Biochemistry and Molecular Biology and Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, Untied States of America
                [25 ]Department of Biochemistry, University of Yaoundé, Yaoundé, Cameroon
                [26 ]CIMUS Research Centre, University of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain
                [27 ]Center for Discovery and Innovation in Parasitic Diseases, Department of Pathology, University of California San Francisco, San Francisco, California, United States of America
                [28 ]Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, University Park, Pennsylvania, United States of America
                [29 ]School of Life and Environmental Sciences, University of Sydney, Darlington New South Wales, Australia
                [30 ]Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
                [31 ]National Center of Advancing Translational Sciences, NIH, Bethesda, Maryland, United States of America
                [32 ]Department of Biochemistry, Mahidol University, Bangkok, Thailand
                [33 ]Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
                [34 ]Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy
                [35 ]Department of Pathology and Immunology, Washington University in St Louis, St. Louis, Missouri, United States of America
                [36 ]Department of Life Sciences, Imperial College London, London, England, United Kingdom
                [37 ]Division of Pharmacology and Drug Discovery, Department of Pediatrics, School of Medicine University of California San Diego, La Jolla, California, United States of America
                [38 ]National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
                [39 ]Department of Biochemistry and Chemistry of nutrition, Mansoura University, Mansoura City, Egypt
                [40 ]Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame Indiana, United States of America
                [41 ]Department of Microbiology & Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
                [42 ]Broad Institute, Cambridge, Massachusetts, United States of America
                [43 ]Biochemistry and Parasitology Department, Malaria DPU, Diseases of the Developing World (DDW), GlaxoSmithKline R&D, Tres Cantos, Madrid, Spain
                [44 ]Tropical Parasitic Diseases Unit, Northwick Park Institute for Medical Research, Harrow, Middlesex, England, United Kingdom
                [45 ]Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America
                [46 ]Medical Scientist Training Program, University of California, San Diego, San Diego, California, United States of America
                [47 ]Department of Chemical Biology & Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
                [48 ]Dept. of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, San Antonio, Texas, United States of America
                [49 ]Instituto de Medicina Molecular, Lisboa, Portugal
                [50 ]Institute of Parasitology, University of Berne, Bern, Switzerland
                [51 ]Medicines for Malaria Venture, Geneva, Switzerland
                [52 ]Global Health Research Section, hhc Data Creation Center, Eisai Co., Ltd, Tsukuba-shi, Ibaraki, Japan
                [53 ]Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire, United Kingdom
                [54 ]Department of Medicine, College of Medicine, University of Vermont, Burlington, Vermont, United States of America
                [55 ]Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok Thailand
                [56 ]Medical Research Centre, Institute for Pharmacogenetics, Essen, Germany
                [57 ]Department of Biochemistry, University of Geneva, Geneva, Switzerland
                [58 ]Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, Louisiana, United States of America
                [59 ]Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia
                [60 ]Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States of America
                [61 ]Department of Medicine, University of California San Diego, San Diego, California, United States of America
                [62 ]Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
                [63 ]University of Antwerp, Department of Biomedical Sciences, Antwerp, Belgium
                [64 ]Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa
                [65 ]Department of Microbiology, Monash University, Clayton, Australia
                [66 ]Chemotargets S.L. and Research Group on Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Institute of Medical Research and University Pompeu Fabra, Barcelona, Catalonia, Spain
                [67 ]Division of Cancer Therapeutics and Diagnosis, Drug Synthesis and Chemistry Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
                [68 ]Graduate Program in Bioinformatics, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
                [69 ]ChEMBL group, European Molecular Biology Laboratory—European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, United Kingdom
                [70 ]Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America
                [71 ]Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura City, Egypt
                [72 ]Department of Biochemistry and Stanford Genome Technology Center, Stanford University, Palo Alto, Calilfornia, United States of America
                [73 ]Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
                [74 ]Laboratoire de Chimie Moléculaire, CNRS,—UMR 7509, COB-IRJBD, Mulhouse Cedex, France
                [75 ]The Jenner Institute, University of Oxford, Oxford, England, United Kingdom
                [76 ]Department of Chemistry, University of Capetown, Capetown, South Africa
                [77 ]H. Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America
                [78 ]Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, California, United States of America
                [79 ]Department of Synthetic Biology and Bioenergy, J. Craig Venter Institute, La Jolla, California, United States of America
                [80 ]School of Natural Sciences, Griffith University, Nathan, Queensland, Australia
                [81 ]Hudson Institute of Medical Research; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
                [82 ]SYNthesis Research, Parkville, Victoria, Australia
                U Tex SouthWestern, UNITED STATES
                Author notes

                The following commercial organizations employ or employed some of the authors, which might be considered a conflict of interest by some readers: BBD BioPhenix SL—BIOBIDE: Aintzane Alday PhD, Ainhoa Alzualde PhD, and, Arantza Muriana; Celia Quevedo PhD; SCYNEXIS, Inc.: Tana Bowling, Audrey Burton, Luke Mercer, and, Bakela Nare PhD; GlaxoSmithKline: Francisco Javier Gamo, PhD, Maria Jose Lafuente, PhD, and Sarah Prats; Eisai Co., Ltd.: Takaaki Horii Ph.D. and Nao-aki Watanabe Ph.D.; Novartis Inc.: Mark Baker PhD MSc (med), and David M. Plouffe; Definiens AG: Andreas Spitzmüller PhD; and, Merck Serono Inc: Thomas Spangenberg PhD.

                Conceived and designed the experiments: WCVV JHA MHA PA AAlz KTA SVA VMA LA MBa SBa CBM SBh QB LB JBo LEB FFB MBr CRC DC MBC GJC SD’A MD JLD SDu MTF JAFR DAF IF FJG BG TG RKG KKH AH TH PH CH II LTJ AK JK SKic KK DEK SLa ML LMa DM NRM SMa SMc SMe JMe RNM JPM BN CN KKO SAP RJQ RSO RSF NGR FS RSi DAS TSo WS YS SJS DTa DTh KFT ST AKT VT JMV AFW EAW EW JBu TSp TW PAW. Performed the experiments: RA VA PA AAld YAR AAls AAlz KTA LA QB TB JBr AB CRC GC MC DC MBC KCCC WC AC BLC DDCL YC GJC NC SD’A MD AYD SDu SAESES IF PVTF AG SG BG GMG RG WAG NG KKH PH TBH KIS MAI AJ ANJ AK TK SKic SKim VPK MJL SLe AML FL DLi LLi MIL AL LLu IL DM NRM SMa SMc IMV SMe LMe ANM FMRdC JMü SNH NN SN KKO DO GPan SPa KP NP SPr DMP SAP AP CQ CAR MAR AR JS NGR MS FSV FS AS SMS SS BMS YS LRYT AT ST AKT VT KOU IU CV EV PVV HV NW KW PMW MW WW NY. Analyzed the data: WCVV JHA RA VA MHA PA AAld YAR AAls AAlz KTA SVA VMA LA MBa SBa CBM SBh QB LB TB JBo LEB FFB JBr MBr AB CRC GC MC DC MBC KCCC WC AC BLC DDCL YC GJC NC SD’A NLD MD JLD AYD SDu SAESES MTF JAFR DAF IF PVTF AG FJG SG BG TG GMG RG WAG NG RKG MAEH KKH AH RHvH TH PH TBH CH II KIS MAI AJ ANJ LTJ RHYJ AK JK TK SKic SKim KK VPK DEK MJL SLa NL SLe AML FL DLi LLi ML MIL AL LLu IL LMa DM NRM SMa SMc IMV SMe LMe JMe ANM RNM FMRdC SMo JPM JMü AM SNH BN CN NN SN KKO DO GPan GPap SPa KP NP SPr DMP SAP AP CQ RJQ CAR MAR AR RSO RSF JS NGR US MS FSV FS RSi DAS TSo AS SMS DJS WS SS BMS YS SJS DTa LRYT AT DTh KFT ST AKT VT KOU IU CV EV JMV PVV HV NW KW PMW AFW EAW EW MW WW NY PHAZ NA BB JBu BL DLe TSp TW PAW. Contributed reagents/materials/analysis tools: AYD. Wrote the paper: WCVV JHA RA VA MHA PA AAld YAR AAls AAlz KTA SVA VMA LA MBa SBa CBM SBh QB LB TB JBo LEB FFB JBr MBr AB CRC GC MC DC MBC KCCC WC AC BLC DDCL YC GJC NC SD’A NLD MD JLD AYD SDu SAESES MTF JAFR DAF IF PVTF AG FJG SG BG TG GMG RG WAG NG RKG MAEH KKH AH RHvH TH PH TBH CH II KIS MAI AJ ANJ LTJ RHYJ AK JK TK SKic SKim KK VPK DEK MJL SLa NL SLe AML FL DLi LLi ML MIL AL LLu IL LMa DM NRM SMa SMc IMV SMe LMe JMe ANM RNM FMRdC SMo JPM JMü AM SNH BN CN NN SN KKO DO GPan GPap SPa KP NP SPr DMP SAP AP CQ RJQ CAR MAR AR RSO RSF JS NGR US MS FSV FS RSi DAS TSo AS SMS DJS WS SS BMS YS SJS DTa LRYT AT DTh KFT ST AKT VT KOU IU CV EV JMV PVV HV NW KW PMW AFW EAW EW MW WW NY PHAZ NA BB JBu BL DLe TSp TW PAW.

                [¤a]

                Current address: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom

                [¤b]

                Current address: Global Health, Merck, Coinsins, Switzerland

                Author information
                http://orcid.org/0000-0002-4611-9205
                http://orcid.org/0000-0002-8451-7044
                Article
                PPATHOGENS-D-16-00679
                10.1371/journal.ppat.1005763
                4965013
                27467575
                6aba15f1-14f4-481c-bc87-2e833ca7c835

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 1 April 2016
                : 21 June 2016
                Page count
                Figures: 2, Tables: 2, Pages: 23
                Funding
                Funded by: UK DFID
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Funded by: funder-id http://dx.doi.org/10.13039/501100004167, Medicines for Malaria Venture;
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Funded by: funder-id http://dx.doi.org/10.13039/501100000923, Australian Research Council;
                Funded by: Bloomberg Family Foundation (US)
                Funded by: funder-id http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Funded by: funder-id http://dx.doi.org/10.13039/501100001322, South African Medical Research Council;
                Funded by: the Council for Scientific and Industrial Research
                Funded by: French ANR program Mammamia
                Thanks to the UK DFID and the Bill and Melinda Gates Foundation Grand Challenges Explorations for providing funding for testing of the Malaria Box and funding the support of individual groups including: Medicines for Malaria Venture MMV Challenge Grant, Grant Numbers MMV 12/0048 and MMV 12/0076 (to JHA), the Australian Research Council (FT10100185 to SAP; FT0991213 to KTA and LP120200557 awarded to VMA), Bill & Melinda Gates Foundation Grant OPP1040394 to PA, OPP1040399 to DAF and VMA and OPP1086189 to KKH, OPP1069393 and OPP1119049 to ML, OPP1024029 to CN, the Bloomberg Family Foundation (JBr), JHMRI for a predoctoral fellowship, the US NIH for the CBI training grant T32GM080189 (to LEB), R01GM104486 (to PAW & WS), R01AI117017 (to JHA) the National Science Foundation Graduate Research Fellowship Program Grant No.DGE-1232825 (DDCL), the South African Medical Research Council Strategic Health Innovation Partnerships (grant V6YBT51 to DM) and the Council for Scientific and Industrial Research (grant V1YTB95, to DM), and the French ANR program Mammamia (ANR-12-BS07-0020-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Parasitic Diseases
                Malaria
                Medicine and Health Sciences
                Tropical Diseases
                Malaria
                Biology and Life Sciences
                Organisms
                Protozoans
                Parasitic Protozoans
                Malarial Parasites
                Biology and Life Sciences
                Parasitology
                Parasite Groups
                Apicomplexa
                Plasmodium
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                Gametocytes
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Drug Discovery
                Medicine and Health Sciences
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                Drug Metabolism
                Biology and Life Sciences
                Toxicology
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                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
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                Physical Sciences
                Chemistry
                Medicinal Chemistry
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                All relevant data are within the paper and its Supporting Information files. Much of the data also appears on ChemBL https://www.ebi.ac.uk/chembl/

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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