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dc.contributor.authorVan Voorhis, Wesley C.
dc.contributor.authorAdams, John H.
dc.contributor.authorAdelfio, Roberto
dc.contributor.authorAhyong, Vida
dc.contributor.authorAkabas, Myles H.
dc.contributor.authorAlano, Pietro
dc.contributor.authorAlday, Aintzane
dc.contributor.authorResto, Yesmalie Aleman
dc.contributor.authorAlsibaee, Aishah
dc.contributor.authorAlzualde, Ainhoa
dc.contributor.authorAndrews, Katherine T.
dc.contributor.authorAvery, Simon V.
dc.contributor.authorAvery, Vicky M.
dc.contributor.authorAyong, Lawrence
dc.contributor.authorBaker, Mark
dc.contributor.authorBaker, Stephen
dc.contributor.authorBen Mamoun, Choukri
dc.contributor.authorBhatia, Sangeeta
dc.contributor.authorBickle, Quentin
dc.contributor.authorBounaadja, Lotfi
dc.contributor.authorBowling, Tana
dc.contributor.authorBosch, Juergen
dc.contributor.authorBoucher, Lauren E.
dc.contributor.authorBoyom, Fabrice F.
dc.contributor.authorBrea, Jose
dc.contributor.authorBrennan, Marian
dc.contributor.authorBurton, Audrey
dc.contributor.authorCaffrey, Conor R.
dc.contributor.authorCamarda, Grazia
dc.contributor.authorCarrasquilla, Manuela
dc.contributor.authorCarter, Dee
dc.contributor.authorCassera, Maria Belen
dc.contributor.authorCheng, Ken Chih-Chien
dc.contributor.authorChindaudomsate, Worathad
dc.contributor.authorChubb, Anthony
dc.contributor.authorColon, Beatrice L.
dc.contributor.authorColon-Lopez, Daisy D.
dc.contributor.authorCorbett, Yolanda
dc.contributor.authorCrowther, Gregory J.
dc.contributor.authorCowan, Noemi
dc.contributor.authorD'Alessandro, Sarah
dc.contributor.authorLe Dang, Na
dc.contributor.authorDelves, Michael
dc.contributor.authorDeRisi, Joseph L.
dc.contributor.authorDu, Alan Y.
dc.contributor.authorDuffy, Sandra
dc.contributor.authorEl-Sayed, Shimaa Abd El-Salam
dc.contributor.authorFerdig, Michael T.
dc.contributor.authorRobledo, Jose A. Fernandez
dc.contributor.authorFidock, David A.
dc.contributor.authorFlorent, Isabelle
dc.contributor.authorFokou, Patrick V. T.
dc.contributor.authorGalstian, Ani
dc.contributor.authorJavier Gamo, Francisco
dc.contributor.authorGokool, Suzanne
dc.contributor.authorGold, Ben
dc.contributor.authorGolub, Todd
dc.contributor.authorGoldgof, Gregory M.
dc.contributor.authorGuha, Rajarshi
dc.contributor.authorGuiguemde, W. Armand
dc.contributor.authorGural, Nil
dc.contributor.authorGuy, R. Kiplin
dc.contributor.authorHansen, Michael A. E.
dc.contributor.authorHanson, Kirsten K.
dc.contributor.authorHemphill, Andrew
dc.contributor.authorvan Huijsduijnen, Rob Hooft
dc.contributor.authorHorii, Takaaki
dc.contributor.authorHorrocks, Paul
dc.contributor.authorHughes, Tyler B.
dc.contributor.authorHuston, Christopher
dc.contributor.authorIgarashi, Ikuo
dc.contributor.authorIngram-Sieber, Katrin
dc.contributor.authorItoe, Maurice A.
dc.contributor.authorJadhav, Ajit
dc.contributor.authorJensen, Amornrat Naranuntarat
dc.contributor.authorJensen, Laran T.
dc.contributor.authorJiang, Rays H. Y.
dc.contributor.authorKaiser, Annette
dc.contributor.authorKeiser, Jennifer
dc.contributor.authorKetas, Thomas
dc.contributor.authorKicka, Sebastien
dc.contributor.authorKim, Sunyoung
dc.contributor.authorKirk, Kiaran
dc.contributor.authorKumar, Vidya P.
dc.contributor.authorKyle, Dennis E.
dc.contributor.authorJose Lafuente, Maria
dc.contributor.authorLandfear, Scott
dc.contributor.authorLee, Nathan
dc.contributor.authorLee, Sukjun
dc.contributor.authorLehane, Adele M.
dc.contributor.authorLi, Fengwu
dc.contributor.authorLittle, David
dc.contributor.authorLiu, Liqiong
dc.contributor.authorLlinas, Manuel
dc.contributor.authorLoza, Maria I.
dc.contributor.authorLubar, Aristea
dc.contributor.authorLucantoni, Leonardo
dc.contributor.authorLucet, Isabelle
dc.contributor.authorMaes, Louis
dc.contributor.authorMancama, Dalu
dc.contributor.authorMansour, Nuha R.
dc.contributor.authorMarch, Sandra
dc.contributor.authorMcGowan, Sheena
dc.contributor.authorVera, Iset Medina
dc.contributor.authorMeister, Stephan
dc.contributor.authorMercer, Luke
dc.contributor.authorMestres, Jordi
dc.contributor.authorMfopa, Alvine N.
dc.contributor.authorMisra, Raj N.
dc.contributor.authorMoon, Seunghyun
dc.contributor.authorMoore, John P.
dc.contributor.authorRodrigues da Costa, Francielly Morais
dc.contributor.authorMueller, Joachim
dc.contributor.authorMuriana, Arantza
dc.contributor.authorHewitt, Stephen Nakazawa
dc.contributor.authorNare, Bakela
dc.contributor.authorNathan, Carl
dc.contributor.authorNarraidoo, Nathalie
dc.contributor.authorNawaratna, Sujeevi
dc.contributor.authorOjo, Kayode K.
dc.contributor.authorOrtiz, Diana
dc.contributor.authorPanic, Gordana
dc.contributor.authorPapadatos, George
dc.contributor.authorParapini, Silvia
dc.contributor.authorPatra, Kailash
dc.contributor.authorNgoc Pham
dc.contributor.authorPrats, Sarah
dc.contributor.authorPlouffe, David M.
dc.contributor.authorPoulsen, Sally-Ann
dc.contributor.authorPradhan, Anupam
dc.contributor.authorQuevedo, Celia
dc.contributor.authorQuinn, Ronald J.
dc.contributor.authorRice, Christopher A.
dc.contributor.authorRizk, Mohamed Abdo
dc.contributor.authorRuecker, Andrea
dc.contributor.authorSt Onge, Robert
dc.contributor.authorFerreira, Rafaela Salgado
dc.contributor.authorSamra, Jasmeet
dc.contributor.authorRobinett, Natalie G.
dc.contributor.authorSchlecht, Ulrich
dc.contributor.authorSchmitt, Marjorie
dc.contributor.authorVillela, Filipe Silva
dc.contributor.authorSilvestrini, Francesco
dc.contributor.authorSinden, Robert
dc.contributor.authorSmith, Dennis A.
dc.contributor.authorSoldati, Thierry
dc.contributor.authorSpitzmueller, Andreas
dc.contributor.authorStamm, Serge Maximilian
dc.contributor.authorSullivan, David J.
dc.contributor.authorSullivan, William
dc.contributor.authorSuresh, Sundari
dc.contributor.authorSuzuki, Brian M.
dc.contributor.authorSuzuki, Yo
dc.contributor.authorSwamidass, S. Joshua
dc.contributor.authorTaramelli, Donatella
dc.contributor.authorTchokouaha, Lauve R. Y.
dc.contributor.authorTheron, Anjo
dc.contributor.authorThomas, David
dc.contributor.authorTonissen, Kathryn F.
dc.contributor.authorTownson, Simon
dc.contributor.authorTripathi, Abhai K.
dc.contributor.authorTrofimov, Valentin
dc.contributor.authorUdenze, Kenneth O.
dc.contributor.authorUllah, Imran
dc.contributor.authorVallieres, Cindy
dc.contributor.authorVigil, Edgar
dc.contributor.authorVinetz, Joseph M.
dc.contributor.authorPhat Voong Vinh
dc.contributor.authorHoan Vu
dc.contributor.authorWatanabe, Nao-aki
dc.contributor.authorWeatherby, Kate
dc.contributor.authorWhite, Pamela M.
dc.contributor.authorWilks, Andrew F.
dc.contributor.authorWinzeler, Elizabeth A.
dc.contributor.authorWojcik, Edward
dc.contributor.authorWree, Melanie
dc.contributor.authorWu, Wesley
dc.contributor.authorYokoyama, Naoaki
dc.contributor.authorZollo, Paul H. A.
dc.contributor.authorAbla, Nada
dc.contributor.authorBlasco, Benjamin
dc.contributor.authorBurrows, Jeremy
dc.contributor.authorLaleu, Benoit
dc.contributor.authorLeroy, Didier
dc.contributor.authorSpangenberg, Thomas
dc.contributor.authorWells, Timothy
dc.contributor.authorWillis, Paul A.
dc.description.abstractA 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.en_US
dc.description.sponsorshipThanks 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.
dc.format.extent23 pages
dc.rightsCreative Commons Attribution 4.0 International
dc.subjectstage plasmodium-falciparumen_US
dc.subjectinfected erythrocytesen_US
dc.subjecttheileria parasitesen_US
dc.titleOpen Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyonden_US
dc.typeArticle - Refereed
dc.title.serialPLOS Pathogens

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Creative Commons Attribution 4.0 International
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