Browsing by Author "Sullivan, David J."

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    Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond
    Van Voorhis, Wesley C.; Adams, John H.; Adelfio, Roberto; Ahyong, Vida; Akabas, Myles H.; Alano, Pietro; Alday, Aintzane; Resto, Yesmalie Aleman; Alsibaee, Aishah; Alzualde, Ainhoa; Andrews, Katherine T.; Avery, Simon V.; Avery, Vicky M.; Ayong, Lawrence; Baker, Mark; Baker, Stephen; Ben Mamoun, Choukri; Bhatia, Sangeeta; Bickle, Quentin; Bounaadja, Lotfi; Bowling, Tana; Bosch, Juergen; Boucher, Lauren E.; Boyom, Fabrice F.; Brea, Jose; Brennan, Marian; Burton, Audrey; Caffrey, Conor R.; Camarda, Grazia; Carrasquilla, Manuela; Carter, Dee; Cassera, Maria B.; Cheng, Ken Chih-Chien; Chindaudomsate, Worathad; Chubb, Anthony; Colon, Beatrice L.; Colon-Lopez, Daisy D.; Corbett, Yolanda; Crowther, Gregory J.; Cowan, Noemi; D'Alessandro, Sarah; Le Dang, Na; Delves, Michael; DeRisi, Joseph L.; Du, Alan Y.; Duffy, Sandra; El-Sayed, Shimaa Abd El-Salam; Ferdig, Michael T.; Robledo, Jose A. Fernandez; Fidock, David A.; Florent, Isabelle; Fokou, Patrick V. T.; Galstian, Ani; Javier Gamo, Francisco; Gokool, Suzanne; Gold, Ben; Golub, Todd; Goldgof, Gregory M.; Guha, Rajarshi; Guiguemde, W. Armand; Gural, Nil; Guy, R. Kiplin; Hansen, Michael A. E.; Hanson, Kirsten K.; Hemphill, Andrew; van Huijsduijnen, Rob Hooft; Horii, Takaaki; Horrocks, Paul; Hughes, Tyler B.; Huston, Christopher; Igarashi, Ikuo; Ingram-Sieber, Katrin; Itoe, Maurice A.; Jadhav, Ajit; Jensen, Amornrat Naranuntarat; Jensen, Laran T.; Jiang, Rays H. Y.; Kaiser, Annette; Keiser, Jennifer; Ketas, Thomas; Kicka, Sebastien; Kim, Sunyoung; Kirk, Kiaran; Kumar, Vidya P.; Kyle, Dennis E.; Jose Lafuente, Maria; Landfear, Scott; Lee, Nathan; Lee, Sukjun; Lehane, Adele M.; Li, Fengwu; Little, David; Liu, Liqiong; Llinas, Manuel; Loza, Maria I.; Lubar, Aristea; Lucantoni, Leonardo; Lucet, Isabelle; Maes, Louis; Mancama, Dalu; Mansour, Nuha R.; March, Sandra; McGowan, Sheena; Vera, Iset Medina; Meister, Stephan; Mercer, Luke; Mestres, Jordi; Mfopa, Alvine N.; Misra, Raj N.; Moon, Seunghyun; Moore, John P.; Rodrigues da Costa, Francielly Morais; Mueller, Joachim; Muriana, Arantza; Hewitt, Stephen Nakazawa; Nare, Bakela; Nathan, Carl; Narraidoo, Nathalie; Nawaratna, Sujeevi; Ojo, Kayode K.; Ortiz, Diana; Panic, Gordana; Papadatos, George; Parapini, Silvia; Patra, Kailash; Ngoc Pham; Prats, Sarah; Plouffe, David M.; Poulsen, Sally-Ann; Pradhan, Anupam; Quevedo, Celia; Quinn, Ronald J.; Rice, Christopher A.; Rizk, Mohamed Abdo; Ruecker, Andrea; St Onge, Robert; Ferreira, Rafaela Salgado; Samra, Jasmeet; Robinett, Natalie G.; Schlecht, Ulrich; Schmitt, Marjorie; Villela, Filipe Silva; Silvestrini, Francesco; Sinden, Robert; Smith, Dennis A.; Soldati, Thierry; Spitzmueller, Andreas; Stamm, Serge Maximilian; Sullivan, David J.; Sullivan, William G.; Suresh, Sundari; Suzuki, Brian M.; Suzuki, Yo; Swamidass, S. Joshua; Taramelli, Donatella; Tchokouaha, Lauve R. Y.; Theron, Anjo; Thomas, David; Tonissen, Kathryn F.; Townson, Simon; Tripathi, Abhai K.; Trofimov, Valentin; Udenze, Kenneth O.; Ullah, Imran; Vallieres, Cindy; Vigil, Edgar; Vinetz, Joseph M.; Phat Voong Vinh; Hoan Vu; Watanabe, Nao-aki; Weatherby, Kate; White, Pamela M.; Wilks, Andrew F.; Winzeler, Elizabeth A.; Wojcik, Edward; Wree, Melanie; Wu, Wesley; Yokoyama, Naoaki; Zollo, Paul H. A.; Abla, Nada; Blasco, Benjamin; Burrows, Jeremy; Laleu, Benoit; Leroy, Didier; Spangenberg, Thomas; Wells, Timothy; Willis, Paul A. (PLOS, 2016-07-28)
    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.
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    Quantitative characterization of hemozoin in Plasmodium berghei and vivax
    Pisciotta, John M.; Scholl, Peter F.; Shuman, Joel L.; Shualev, Vladimir; Sullivan, David J. (Elsevier, 2017-04-01)
    The incidence and global distribution of chloroquine resistant (CR) Plasmodium vivax infection has increased since emerging in 1989. The mechanism of resistance in CR P. vivax has not been defined. The resistance likely relates to the formation and disposition of hemozoin as chloroquine's primary mechanism of action involves disruption of hemozoin formation. CR P. berghei strains, like CR P. vivax strains, are confined to reticulocyte host cells and reportedly they do not accumulate appreciable intraerythrocytic hemozoin. Reports comparing hemozoin production between P. vivax strains and CR to chloroquine sensitive (CS) P. berghei are absent. Here we compare in vivo patterns of hemozoin formation and distribution in blood, spleen and liver tissue of male Swiss mice infected with CS or CR P. berghei not treated with chloroquine and CR P. berghei also treated with chloroquine. Light microscopy, laser desorption mass spectrometry and a colorimetric hemozoin assay detect trace hemozoin in the blood of CR P. berghei infected mice but significant hemozoin accumulation in liver and spleen tissue. Field emission in lens scanning electron microscopy reveals CR P. berghei hemozoin crystals are morphologically smaller but similar to those formed by CS parasites. CR P. berghei produces approximately five-fold less total hemozoin than CS strain. Lipid analysis of CS and CR P. berghei sucrose gradient purified bloodstage hemozoin indicates a similar lipid environment around the isolated hemozoin, predominately monopalmitic glycerol and monostearic glycerol. In contrast to CR and CS P. berghei, colorimetric hemozoin analysis of P. vivax strains indicates similar amounts of hemozoin are produced despite differing chloroquine sensitivities. These results suggest CR P. berghei forms significant hemozoin which accumulates in liver and spleen tissues and that the P. vivax chloroquine resistance mechanism differs from P. berghei.