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3. An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms

Author

Hart, Thomas M., Sonnert, Nicole D., Tang, Xiaotian, Chaurasia, Reetika, Allen, Paige E., Hunt, Jason R., Read, Curtis B., Johnson, Emily E., Arora, Gunjan, Dai, Yile, Cui, Yingjun, Chuang, Yu-Min, Yu, Qian, Rahman, M. Sayeedur, Mendes, M. Tays, Rolandelli, Agustin, Singh, Pallavi, Tripathi, Abhai K., Ben Mamoun, Choukri, Caimano, Melissa J., Radolf, Justin D., Lin, Yi-Pin, Fingerle, Volker, Margos, Gabriele, Pal, Utpal, Johnson, Raymond M., Pedra, Joao H.F., Azad, Abdu F., Salje, Jeanne, Dimopoulos, George, Vinetz, Joseph M., Carlyon, Jason A., Palm, Noah W., Fikrig, Erol, and Ring, Aaron M.

Published
2024
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5. Novel insights into the role of long non-coding RNA in the human malaria parasite, Plasmodium falciparum

Author

Batugedara, Gayani, Lu, Xueqing M., Hristov, Borislav, Abel, Steven, Chahine, Zeinab, Hollin, Thomas, Williams, Desiree, Wang, Tina, Cort, Anthony, Lenz, Todd, Thompson, Trevor A., Prudhomme, Jacques, Tripathi, Abhai K., Xu, Guoyue, Cudini, Juliana, Dogga, Sunil, Lawniczak, Mara, Noble, William Stafford, Sinnis, Photini, and Le Roch, Karine G.

Published
2023
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7. A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin

Author

Qiu, Deyun, Pei, Jinxin V., Rosling, James E. O., Thathy, Vandana, Li, Dongdi, Xue, Yi, Tanner, John D., Penington, Jocelyn Sietsma, Aw, Yi Tong Vincent, Aw, Jessica Yi Han, Xu, Guoyue, Tripathi, Abhai K., Gnadig, Nina F., Yeo, Tomas, Fairhurst, Kate J., Stokes, Barbara H., Murithi, James M., Kümpornsin, Krittikorn, Hasemer, Heath, Dennis, Adelaide S. M., Ridgway, Melanie C., Schmitt, Esther K., Straimer, Judith, Papenfuss, Anthony T., Lee, Marcus C. S., Corry, Ben, Sinnis, Photini, Fidock, David A., van Dooren, Giel G., Kirk, Kiaran, and Lehane, Adele M.

Published
2022
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9. Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Author

Mok, Sachel, primary, Yeo, Tomas, additional, Hong, Davin, additional, Shears, Melanie J., additional, Ross, Leila S., additional, Ward, Kurt E., additional, Dhingra, Satish K., additional, Kanai, Mariko, additional, Bridgford, Jessica L., additional, Tripathi, Abhai K., additional, Mlambo, Godfree, additional, Burkhard, Anna Y., additional, Ansbro, Megan R., additional, Fairhurst, Kate J., additional, Gil-Iturbe, Eva, additional, Park, Heekuk, additional, Rozenberg, Felix D., additional, Kim, Jonathan, additional, Mancia, Filippo, additional, Fairhurst, Rick M., additional, Quick, Matthias, additional, Uhlemann, Anne-Catrin, additional, Sinnis, Photini, additional, and Fidock, David A., additional

Published
2023
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10. Chemical genetics of Plasmodium falciparum

Author

Guiguemde, W Armand, Shelat, Anang A, Bouck, David, Duffy, Sandra, Crowther, Gregory J, Davis, Paul H, Smithson, David C, Connelly, Michele, Clark, Julie, Zhu, Fangyi, Jiménez-Díaz, María B, Martinez, María S, Wilson, Emily B, Tripathi, Abhai K, Gut, Jiri, Sharlow, Elizabeth R, Bathurst, Ian, Mazouni, Farah El, Fowble, Joseph W, Forquer, Isaac, McGinley, Paula L, Castro, Steve, Angulo-Barturen, Iñigo, Ferrer, Santiago, Rosenthal, Philip J, DeRisi, Joseph L, Sullivan, David J, Lazo, John S, Roos, David S, Riscoe, Michael K, Phillips, Margaret A, Rathod, Pradipsinh K, Van Voorhis, Wesley C, Avery, Vicky M, and Guy, R Kiplin

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Biotechnology, Antimicrobial Resistance, Rare Diseases, Infectious Diseases, Emerging Infectious Diseases, Genetics, Orphan Drug, Malaria, Biodefense, Vector-Borne Diseases, 5.1 Pharmaceuticals, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Animals, Antimalarials, Cell Line, Drug Discovery, Drug Evaluation, Preclinical, Drug Resistance, Drug Therapy, Combination, Erythrocytes, Humans, Malaria, Falciparum, Mice, Phenotype, Phylogeny, Plasmodium falciparum, Reproducibility of Results, Small Molecule Libraries, General Science & Technology
Abstract

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used 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 showed potent in vitro activity against drug-resistant P. falciparum 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 several 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. Our findings provide the scientific community with new starting points for malaria drug discovery.

Published
2010

12. Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Author

Mok, Sachel, Yeo, Tomas, Hong, Davin, Shears, Melanie J., Ross, Leila S., Ward, Kurt E., Dhingra, Satish K., Kanai, Mariko, Bridgford, Jessica L., Tripathi, Abhai K., Mlambo, Godfree, Burkhard, Anna Y., Fairhurst, Kate J., Gil-Iturbe, Eva, Park, Heekuk, Rozenberg, Felix D., Kim, Jonathan, Mancia, Filippo, Quick, Matthias, Uhlemann, Anne-Catrin, Sinnis, Photini, and Fidock, David A.

Subjects
Article
Abstract

Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

Published
2023

13. Transmissibility of clinically relevant atovaquone-resistantPlasmodium falciparumby anopheline mosquitoes

Author

Balta, Victoria A., primary, Stiffler, Deborah, additional, Sayeed, Abeer, additional, Tripathi, Abhai K., additional, Elahi, Rubayet, additional, Mlambo, Godfree, additional, Bakshi, Rahul P., additional, Dziedzic, Amanda G., additional, Jedlicka, Anne E., additional, Nenortas, Elizabeth, additional, Romero-Rodriguez, Keyla, additional, Canonizado, Matthew A., additional, Mann, Alexis, additional, Owen, Andrew, additional, Sullivan, David J., additional, Prigge, Sean T., additional, Sinnis, Photini, additional, and Shapiro, Theresa A., additional

Published
2023
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14. Deciphering the non-coding code of pathogenicity and sexual differentiation in the human malaria parasite

Author

Batugedara, Gayani, primary, Lu, Xueqing M., additional, Abel, Steven, additional, Chahine, Zeinab, additional, Hristov, Borislav, additional, Williams, Desiree, additional, Hollin, Thomas, additional, Wang, Tina, additional, Cort, Anthony, additional, Lenz, Todd, additional, Thompson, Trevor, additional, Prudhomme, Jacques, additional, Tripathi, Abhai K., additional, Xu, Guoyue, additional, Cudini, Juliana, additional, Dogga, Sunil, additional, Lawniczak, Mara, additional, Stafford Noble, William, additional, Sinnis, Photini, additional, and Le Roch, Karine G., additional

Published
2022
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21. Correction: Cao et al. Effective Functional Immunogenicity of a DNA Vaccine Combination Delivered via In Vivo Electroporation Targeting Malaria Infection and Transmission. Vaccines 2022, 10 , 1134.

Author

Cao, Yi, Hayashi, Clifford T. H., Zavala, Fidel, Tripathi, Abhai K., Simonyan, Hayk, Young, Colin N., Clark, Leor C., Usuda, Yukari, Van Parys, Jacob M., and Kumar, Nirbhay

Subjects
DNA vaccines, VACCINE immunogenicity, DNA sequencing, COMBINED vaccines, INFECTIOUS disease transmission
Abstract

This document is a correction notice for an article titled "Effective Functional Immunogenicity of a DNA Vaccine Combination Delivered via In Vivo Electroporation Targeting Malaria Infection and Transmission." The authors of the article identified a minor error in the description of the DNA plasmid used in the study. The correction clarifies that the presence or absence of certain glycosylation sites in the plasmid does not impact the scientific validity of the results or conclusions. The authors state that the scientific conclusions remain unchanged despite this error. [Extracted from the article]

Published
2024
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23. A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin.

Author

Qiu, Deyun, Pei, Jinxin V., Rosling, James E. O., Thathy, Vandana, Li, Dongdi, Xue, Yi, Tanner, John D., Penington, Jocelyn Sietsma, Aw, Yi Tong Vincent, Aw, Jessica Yi Han, Xu, Guoyue, Tripathi, Abhai K., Gnadig, Nina F., Yeo, Tomas, Fairhurst, Kate J., Stokes, Barbara H., Murithi, James M., Kümpornsin, Krittikorn, Hasemer, Heath, and Dennis, Adelaide S. M.

Subjects
PLASMODIUM falciparum, PLASMODIUM, ORAL drug administration, PARASITES, TOXOPLASMA gondii, ADENOSINE triphosphatase
Abstract

Diverse compounds target the Plasmodium falciparum Na+ pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4G358S parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na+ regulation. The G358S mutation reduces the affinity of PfATP4 for Na+ and is associated with an increase in the parasite's resting cytosolic [Na+]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development. In a recent clinical trial for oral administration of cipargamin in individuals with malaria, there was an emergence of recrudescent parasites with a G358S mutation in PfATP4. In this work, the authors investigate the effect of this mutation on the function of the ATPase, on parasite growth and susceptibility to antimalarial drugs. [ABSTRACT FROM AUTHOR]

Published
2022
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24. Plasmodium falciparum Pf77 and male development gene 1 as vaccine antigens that induce potent transmission-reducing antibodies

Author

Tripathi, Abhai K., primary, Oakley, Miranda S., additional, Verma, Nitin, additional, Mlambo, Godfree, additional, Zheng, Hong, additional, Meredith, Scott M., additional, Essuman, Edward, additional, Puri, Ankit, additional, Skelton, Richard A., additional, Takeda, Kazuyo, additional, Majam, Victoria, additional, Quakyi, Isabella A., additional, Locke, Emily, additional, Morin, Merribeth, additional, Miura, Kazutoyo, additional, Long, Carole A., additional, and Kumar, Sanjai, additional

Published
2021
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26. Plasmodium falciparum Gametocyte Culture and Mosquito Infection Through Artificial Membrane Feeding

Author

Tripathi, Abhai K, Mlambo, Godfree, Kanatani, Sachie, Sinnis, Photini, and Dimopoulos, George

Subjects
fungi, parasitic diseases, Anopheles, Plasmodium falciparum, Animals, Humans, Female, Membranes, Artificial, Mosquito Vectors, Malaria, Falciparum, Article
Abstract

Malaria remains one of the most important public health problems, causing significant morbidity and mortality. Malaria is a mosquito borne disease transmitted through an infectious bite from the female Anopheles mosquito. Malaria control will eventually rely on a multitude of approaches, which includes ways to block transmission to, through and from mosquitoes. To study mosquito stages of malaria parasites in the laboratory, we have optimized a protocol to culture highly infectious Plasmodium falciparum gametocytes, a parasite stage required for transmission from the human host to the mosquito vector. P. falciparum gametocytes mature through five morphologically distinct steps, which takes approximately 1-2 weeks. Gametocyte culture described in this protocol is completed in 15 days and are infectious to mosquitoes from days 15-18. These protocols were developed to maintain a continuous cycle of infection competent gametocytes and to maintain uninterrupted supply of mosquito stages of the parasite. Here, we describe the methodology of gametocyte culture and how to infect mosquitoes with these parasites using glass membrane feeders.

Published
2020

31. A mosquito salivary gland protein partially inhibits Plasmodium sporozoite cell traversal and transmission

Author

Schleicher, Tyler R., primary, Yang, Jing, additional, Freudzon, Marianna, additional, Rembisz, Alison, additional, Craft, Samuel, additional, Hamilton, Madeleine, additional, Graham, Morven, additional, Mlambo, Godfree, additional, Tripathi, Abhai K., additional, Li, Yue, additional, Cresswell, Peter, additional, Sinnis, Photini, additional, Dimopoulos, George, additional, and Fikrig, Erol, additional

Published
2018
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33. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Bhatia, Sangeeta N, Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Yesmalie, Alemán Resto, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria Belen, Ken, Chih-Chien Cheng, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, 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, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, 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, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, 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., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, 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., Voong Vinh, Phat, Vu, Hoan, 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, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, Willis, Paul A., Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Bhatia, Sangeeta N, Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, Yesmalie, Alemán Resto, Alsibaee, Aishah, Alzualde, Ainhoa, Andrews, Katherine T., Avery, Simon V., Avery, Vicky M., Ayong, Lawrence, Baker, Mark, Baker, Stephen, Ben Mamoun, Choukri, Bickle, Quentin, Bounaadja, Lotfi, Bowling, Tana, Bosch, Jürgen, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Cassera, Maria Belen, Ken, Chih-Chien Cheng, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Colón-López, 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, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fernández Robledo, José A., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, 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, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, 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., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Llinás, Manuel, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Müller, Joachim, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Spitzmüller, Andreas, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, 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., Voong Vinh, Phat, Vu, Hoan, 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, Benoît, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

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 chemis

Published
2017

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

Author

Phillips, Margaret A., Van Voorhis, Wesley C., Adams, John H., Adelfio, Roberto, Ahyong, Vida, Akabas, Myles H., Alano, Pietro, Alday, Aintzane, 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, Boucher, Lauren E., Boyom, Fabrice F., Brea, Jose, Brennan, Marian, Burton, Audrey, Caffrey, Conor R., Camarda, Grazia, Carrasquilla, Manuela, Carter, Dee, Belen Cassera, Maria, Chih-Chien Cheng, Ken, Chindaudomsate, Worathad, Chubb, Anthony, Colon, Beatrice L., Corbett, Yolanda, Crowther, Gregory J., Cowan, Noemi, Le Dang, Na, Delves, Michael, DeRisi, Joseph L., Du, Alan Y., Duffy, Sandra, Abd El-Salam El-Sayed, Shimaa, Ferdig, Michael T., Fidock, David A., Florent, Isabelle, Fokou, Patrick V. T., Galstian, Ani, Gamo, Francisco Javier, 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, Hooft van Huijsduijnen, Rob, Horii, Takaaki, Horrocks, Paul, Hughes, Tyler B., Huston, Christopher, Igarashi, Ikuo, Ingram-Sieber, Katrin, Itoe, Maurice A., Jadhav, Ajit, Naranuntarat Jensen, Amornrat, 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., Lafuente, Maria Jose, Landfear, Scott, Lee, Nathan, Lee, Sukjun, Lehane, Adele M., Li, Fengwu, Little, David, Liu, Liqiong, Loza, Maria I., Lubar, Aristea, Lucantoni, Leonardo, Lucet, Isabelle, Maes, Louis, Mancama, Dalu, Mansour, Nuha R., March, Sandra, McGowan, Sheena, Medina Vera, Iset, Meister, Stephan, Mercer, Luke, Mestres, Jordi, Mfopa, Alvine N., Misra, Raj N., Moon, Seunghyun, Moore, John P., Morais Rodrigues da Costa, Francielly, Muriana, Arantza, Nakazawa Hewitt, Stephen, Nare, Bakela, Nathan, Carl, Narraidoo, Nathalie, Nawaratna, Sujeevi, Ojo, Kayode K., Ortiz, Diana, Panic, Gordana, Papadatos, George, Parapini, Silvia, Patra, Kailash, Pham, Ngoc, Prats, Sarah, Plouffe, David M., Poulsen, Sally-Ann, Pradhan, Anupam, Quevedo, Celia, Quinn, Ronald J., Rice, Christopher A., Abdo Rizk, Mohamed, Ruecker, Andrea, St. Onge, Robert, Salgado Ferreira, Rafaela, Samra, Jasmeet, Robinett, Natalie G., Schlecht, Ulrich, Schmitt, Marjorie, Silva Villela, Filipe, Silvestrini, Francesco, Sinden, Robert, Smith, Dennis A., Soldati, Thierry, Stamm, Serge Maximilian, Sullivan, David J., Sullivan, William, 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., Voong Vinh, Phat, Vu, Hoan, 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, Leroy, Didier, Spangenberg, Thomas, Wells, Timothy, and Willis, Paul A.

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.

Published
2016

37. Erratum: Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony

Author

Ganter, Markus, primary, Goldberg, Jonathan M., additional, Dvorin, Jeffrey D., additional, Paulo, Joao A., additional, King, Jonas G., additional, Tripathi, Abhai K., additional, Paul, Aditya S., additional, Yang, Jing, additional, Coppens, Isabelle, additional, Jiang, Rays H. Y., additional, Elsworth, Brendan, additional, Baker, David A., additional, Dinglasan, Rhoel R., additional, Gygi, Steven P., additional, and Duraisingh, Manoj T., additional

Published
2017
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38. Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony

Author

Ganter, Markus, primary, Goldberg, Jonathan M., additional, Dvorin, Jeffrey D., additional, Paulo, Joao A., additional, King, Jonas G., additional, Tripathi, Abhai K., additional, Paul, Aditya S., additional, Yang, Jing, additional, Coppens, Isabelle, additional, Jiang, Rays H. Y., additional, Elsworth, Brendan, additional, Baker, David A., additional, Dinglasan, Rhoel R., additional, Gygi, Steven P., additional, and Duraisingh, Manoj T., additional

Published
2017
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39. Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites

Author

Oakley, Miranda S., primary, Verma, Nitin, additional, Zheng, Hong, additional, Anantharaman, Vivek, additional, Takeda, Kazuyo, additional, Gao, Yamei, additional, Myers, Timothy G., additional, Pham, Phuong Thao, additional, Mahajan, Babita, additional, Kumar, Nirbhay, additional, Sangweme, Davison, additional, Tripathi, Abhai K., additional, Mlambo, Godfree, additional, Aravind, L., additional, and Kumar, Sanjai, additional

Published
2016
Full Text
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42. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond

Author

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., 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, and Willis, Paul A.

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 chemis

Published
2016
Full Text
View/download PDF

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

Author

Biochemistry, Center for Drug Discovery, 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., Biochemistry, Center for Drug Discovery, 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, and Willis, Paul A.

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 chemis

Published
2016

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

Author

Van Voorhis, Wesley C., primary, Adams, John H., additional, Adelfio, Roberto, additional, Ahyong, Vida, additional, Akabas, Myles H., additional, Alano, Pietro, additional, Alday, Aintzane, additional, Alemán Resto, Yesmalie, additional, Alsibaee, Aishah, additional, Alzualde, Ainhoa, additional, Andrews, Katherine T., additional, Avery, Simon V., additional, Avery, Vicky M., additional, Ayong, Lawrence, additional, Baker, Mark, additional, Baker, Stephen, additional, Ben Mamoun, Choukri, additional, Bhatia, Sangeeta, additional, Bickle, Quentin, additional, Bounaadja, Lotfi, additional, Bowling, Tana, additional, Bosch, Jürgen, additional, Boucher, Lauren E., additional, Boyom, Fabrice F., additional, Brea, Jose, additional, Brennan, Marian, additional, Burton, Audrey, additional, Caffrey, Conor R., additional, Camarda, Grazia, additional, Carrasquilla, Manuela, additional, Carter, Dee, additional, Belen Cassera, Maria, additional, Chih-Chien Cheng, Ken, additional, Chindaudomsate, Worathad, additional, Chubb, Anthony, additional, Colon, Beatrice L., additional, Colón-López, Daisy D., additional, Corbett, Yolanda, additional, Crowther, Gregory J., additional, Cowan, Noemi, additional, D’Alessandro, Sarah, additional, Le Dang, Na, additional, Delves, Michael, additional, DeRisi, Joseph L., additional, Du, Alan Y., additional, Duffy, Sandra, additional, Abd El-Salam El-Sayed, Shimaa, additional, Ferdig, Michael T., additional, Fernández Robledo, José A., additional, Fidock, David A., additional, Florent, Isabelle, additional, Fokou, Patrick V. T., additional, Galstian, Ani, additional, Gamo, Francisco Javier, additional, Gokool, Suzanne, additional, Gold, Ben, additional, Golub, Todd, additional, Goldgof, Gregory M., additional, Guha, Rajarshi, additional, Guiguemde, W. Armand, additional, Gural, Nil, additional, Guy, R. Kiplin, additional, Hansen, Michael A. E., additional, Hanson, Kirsten K., additional, Hemphill, Andrew, additional, Hooft van Huijsduijnen, Rob, additional, Horii, Takaaki, additional, Horrocks, Paul, additional, Hughes, Tyler B., additional, Huston, Christopher, additional, Igarashi, Ikuo, additional, Ingram-Sieber, Katrin, additional, Itoe, Maurice A., additional, Jadhav, Ajit, additional, Naranuntarat Jensen, Amornrat, additional, Jensen, Laran T., additional, Jiang, Rays H. Y., additional, Kaiser, Annette, additional, Keiser, Jennifer, additional, Ketas, Thomas, additional, Kicka, Sebastien, additional, Kim, Sunyoung, additional, Kirk, Kiaran, additional, Kumar, Vidya P., additional, Kyle, Dennis E., additional, Lafuente, Maria Jose, additional, Landfear, Scott, additional, Lee, Nathan, additional, Lee, Sukjun, additional, Lehane, Adele M., additional, Li, Fengwu, additional, Little, David, additional, Liu, Liqiong, additional, Llinás, Manuel, additional, Loza, Maria I., additional, Lubar, Aristea, additional, Lucantoni, Leonardo, additional, Lucet, Isabelle, additional, Maes, Louis, additional, Mancama, Dalu, additional, Mansour, Nuha R., additional, March, Sandra, additional, McGowan, Sheena, additional, Medina Vera, Iset, additional, Meister, Stephan, additional, Mercer, Luke, additional, Mestres, Jordi, additional, Mfopa, Alvine N., additional, Misra, Raj N., additional, Moon, Seunghyun, additional, Moore, John P., additional, Morais Rodrigues da Costa, Francielly, additional, Müller, Joachim, additional, Muriana, Arantza, additional, Nakazawa Hewitt, Stephen, additional, Nare, Bakela, additional, Nathan, Carl, additional, Narraidoo, Nathalie, additional, Nawaratna, Sujeevi, additional, Ojo, Kayode K., additional, Ortiz, Diana, additional, Panic, Gordana, additional, Papadatos, George, additional, Parapini, Silvia, additional, Patra, Kailash, additional, Pham, Ngoc, additional, Prats, Sarah, additional, Plouffe, David M., additional, Poulsen, Sally-Ann, additional, Pradhan, Anupam, additional, Quevedo, Celia, additional, Quinn, Ronald J., additional, Rice, Christopher A., additional, Abdo Rizk, Mohamed, additional, Ruecker, Andrea, additional, St. Onge, Robert, additional, Salgado Ferreira, Rafaela, additional, Samra, Jasmeet, additional, Robinett, Natalie G., additional, Schlecht, Ulrich, additional, Schmitt, Marjorie, additional, Silva Villela, Filipe, additional, Silvestrini, Francesco, additional, Sinden, Robert, additional, Smith, Dennis A., additional, Soldati, Thierry, additional, Spitzmüller, Andreas, additional, Stamm, Serge Maximilian, additional, Sullivan, David J., additional, Sullivan, William, additional, Suresh, Sundari, additional, Suzuki, Brian M., additional, Suzuki, Yo, additional, Swamidass, S. Joshua, additional, Taramelli, Donatella, additional, Tchokouaha, Lauve R. Y., additional, Theron, Anjo, additional, Thomas, David, additional, Tonissen, Kathryn F., additional, Townson, Simon, additional, Tripathi, Abhai K., additional, Trofimov, Valentin, additional, Udenze, Kenneth O., additional, Ullah, Imran, additional, Vallieres, Cindy, additional, Vigil, Edgar, additional, Vinetz, Joseph M., additional, Voong Vinh, Phat, additional, Vu, Hoan, additional, Watanabe, Nao-aki, additional, Weatherby, Kate, additional, White, Pamela M., additional, Wilks, Andrew F., additional, Winzeler, Elizabeth A., additional, Wojcik, Edward, additional, Wree, Melanie, additional, Wu, Wesley, additional, Yokoyama, Naoaki, additional, Zollo, Paul H. A., additional, Abla, Nada, additional, Blasco, Benjamin, additional, Burrows, Jeremy, additional, Laleu, Benoît, additional, Leroy, Didier, additional, Spangenberg, Thomas, additional, Wells, Timothy, additional, and Willis, Paul A., additional

Published
2016
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