Open Access
Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond
Wesley C. Van Voorhis,John H. Adams,Roberto Adelfio,Vida Ahyong,Myles H. Akabas,Pietro Alano,Aintzane Alday,Alemán Resto Yesmalie,Aishah Alsibaee,Ainhoa Alzualde,Katherine T. Andrews,Simon V. Avery,Vicky M. Avery,Lawrence Ayong,Mark Baker,Stephen Baker,Choukri Ben Mamoun,Quentin D. Bickle,Lotfi Bounaadja,Tana Bowling,Jürgen Bosch,Lauren E. Boucher,Fabrice Fekam Boyom,José Brea,Marian P. Brennan,Audrey Burton,Conor R. Caffrey,Grazia Camarda,Manuela Carrasquilla,Dee A. Carter,Maria B. Cassera,Chih-Chien Cheng Ken,Worathad Chindaudomsate,Anthony J. Chubb,Beatrice L. Colon,Daisy D. Colón-López,Yolanda Corbett,Gregory J. Crowther,Noemi Cowan,Sarah D'Alessandro,Na Le Dang,Michael J. Delves,Joseph L. DeRisi,Alan Y. Du,Sandra Duffy,Shimaa Abd El-Salam El-Sayed,Michael T. Ferdig,José A. Fernández Robledo,David A. Fidock,Isabelle Florent,Patrick Valere Tsouh Fokou,Ani Galstian,Francisco-Javier Gamo,Suzanne Gokool,Ben Gold,Todd R. Golub,Gregory M. Goldgof,Rajarshi Guha,W. Armand Guiguemde,Nil Gural,R. Kiplin Guy,Michael Adsetts Edberg Hansen,Kirsten K. Hanson,Andrew Hemphill,Rob Hooft van Huijsduijnen,Takaaki Horii,Paul Horrocks,Tyler B. Hughes,Christopher D. Huston,Ikuo Igarashi,Katrin Ingram-Sieber,Maurice A. Itoe,Ajit Jadhav,Amornrat Naranuntarat Jensen,Laran T. Jensen,Rays H. Y. Jiang,Annette Kaiser,Jennifer Keiser,Thomas J. Ketas,Sébastien Kicka,Sunyoung Kim,Kiaran Kirk,Vidya Prasanna Kumar,Dennis E. Kyle,Maria Jose Lafuente,Scott M. Landfear,Nathan Lee,Sukjun Lee,Adele M. Lehane,Fengwu Li,David Little,Liqiong Liu,Manuel Llinás,María Isabel Loza,Aristea Lubar,Leonardo Lucantoni,Isabelle S Lucet,Louis Maes,Dalu Mancama,Nuha R. Mansour,Sandra March,Sheena McGowan,Iset Medina Vera,Stephan Meister,Luke Mercer,Jordi Mestres,Alvine Ngoutane Mfopa,Raj N. Misra,Seung-Hyun Moon,John P. Moore,Francielly Morais Rodrigues da Costa,Joachim Müller,Arantza Muriana,Stephen N. Hewitt,Bakela Nare,Carl Nathan,Nathalie Narraidoo,Sujeevi Nawaratna,Kayode K. Ojo,Diana Ortiz,Gordana Panic,George Papadatos,Silvia Parapini,Kailash P. Patra,Ngoc Minh Pham,Sarah Prats,David Plouffe,Sally-Ann Poulsen,Anupam Pradhan,Celia Quevedo,Ronald J. Quinn,Christopher A. Rice,Andrea Ruecker,Robert P. St.Onge,Rafaela Salgado Ferreira,Jasmeet Samra,Natalie G. Robinett,Ulrich Schlecht,Marjorie Schmitt,Filipe Silva Villela,Francesco Silvestrini,Robert E. Sinden,Dennis A. Smith,Thierry Soldati,Andreas Spitzmüller,Serge Maximilian Stamm,David J. Sullivan,William J. Sullivan,Sundari Suresh,Brian M. Suzuki,Yo Suzuki,S. Joshua Swamidass,Donatella Taramelli,Lauve R. Y. Tchokouaha,Anjo Theron,David Thomas,Kathryn F. Tonissen,Simon Townson,Abhai K. Tripathi,Valentin Trofimov,Kenneth O. Udenze,Imran Ullah,Cindy Vallières,Edgar Vigil,Joseph M. Vinetz,Phat Voong Vinh,Hoan Vu,Nao-aki Watanabe,Kate Weatherby,Pamela M. White,Andrew F. Wilks,Elizabeth A. Winzeler,Edward J. Wojcik,Melanie Wree,Wesley Wu,Naoaki Yokoyama,Paul Henri Amvam Zollo,Nada Abla,Benjamin Blasco,Jeremy N. Burrows,Benoît Laleu,Didier Leroy,Thomas Spangenberg,Timothy N. C. Wells,Paul Willis,Sangeeta N. Bhatia +185 more
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TLDR
The Medicines for Malaria Venture Malaria Box as mentioned in this paper 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.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.read more
Citations
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Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis
Min Zhang,Chengqi Wang,Thomas D. Otto,Jenna Oberstaller,Xiangyun Liao,Swamy R. Adapa,Kenneth O. Udenze,Iraad F. Bronner,Deborah Casandra,Matthew Mayho,Jacqueline Brown,Suzanne Li,Justin Swanson,Julian C. Rayner,Rays H. Y. Jiang,John H. Adams +15 more
TL;DR: Saturation-scale mutagenesis allows prioritization of intervention targets in the genome of the most important cause of malaria, and confirms the proteasome-degradation pathway is a high-value druggable target.
Journal ArticleDOI
CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naïve Melanoma Patients and Expand Significantly During Anti–PD-1 Treatment
Jarem Edwards,James S. Wilmott,Jason Madore,Tuba N. Gide,Camelia Quek,Annie Tasker,Angela Ferguson,Jinbiao Chen,Rehana Hewavisenti,Peter Hersey,Thomas Gebhardt,Wolfgang Weninger,Warwick J. Britton,Robyn P. M. Saw,Robyn P. M. Saw,John F. Thompson,John F. Thompson,Alexander M. Menzies,Alexander M. Menzies,Georgina V. Long,Georgina V. Long,Richard A. Scolyer,Richard A. Scolyer,Umaimainthan Palendira +23 more
TL;DR: Tumor-resident CD8-cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma and are likely to initiate response to anti–PD-1 and anti–LAG-3 treatments, and it is proposed that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.
Journal ArticleDOI
The past, present and future of anti-malarial medicines
TL;DR: The range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine.
Journal ArticleDOI
The viral protein corona directs viral pathogenesis and amyloid aggregation
Kariem Ezzat,Kariem Ezzat,Maria Pernemalm,Sandra Pålsson,Thomas C. Roberts,Thomas C. Roberts,Peter Järver,Aleksandra Dondalska,Burcu Bestas,Michał J. Sobkowiak,Bettina Levänen,Magnus Sköld,Magnus Sköld,Elizabeth A. Thompson,Osama Saher,Osama Saher,Otto K. Kari,Tatu Lajunen,Eva Sverremark Ekström,Caroline Nilsson,Yevheniia Ishchenko,Tarja Malm,Matthew J.A. Wood,Ultan F. Power,Sergej Masich,Anders Lindén,Anders Lindén,Johan K. Sandberg,Janne Lehtiö,Anna-Lena Spetz,Samir El Andaloussi,Samir El Andaloussi +31 more
TL;DR: It is shown that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids, and that corona pre-coating differentially affects viral infectivity and immune cell activation.
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