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205. 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

208. 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., and Alano, Pietro

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

209. 5-Aminopyrazole-4-Carboxamide-Based Compounds Prevent the Growth of Cryptosporidium parvum

Author

Huang, Wenlin, primary, Choi, Ryan, additional, Hulverson, Matthew A., additional, Zhang, Zhongsheng, additional, McCloskey, Molly C., additional, Schaefer, Deborah A., additional, Whitman, Grant R., additional, Barrett, Lynn K., additional, Vidadala, Rama Subba Rao, additional, Riggs, Michael W., additional, Maly, Dustin J., additional, Van Voorhis, Wesley C., additional, Ojo, Kayode K., additional, and Fan, Erkang, additional

Published
2017
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210. Susceptibility Testing of Medically Important Parasites

Author

Genetu Bayih, Abebe, primary, Debnath, Anjan, additional, Mitre, Edward, additional, Huston, Christopher D., additional, Laleu, Benoît, additional, Leroy, Didier, additional, Blasco, Benjamin, additional, Campo, Brice, additional, Wells, Timothy N. C., additional, Willis, Paul A., additional, Sjö, Peter, additional, Van Voorhis, Wesley C., additional, and Pillai, Dylan R., additional

Published
2017
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211. Recombinant human G6PD for quality control and quality assurance of novel point-of-care diagnostics for G6PD deficiency

Author

Kahn, Maria, primary, LaRue, Nicole, additional, Zhu, Changcheng, additional, Pal, Sampa, additional, Mo, Jack S., additional, Barrett, Lynn K., additional, Hewitt, Steve N., additional, Dumais, Mitchell, additional, Hemmington, Sandra, additional, Walker, Adrian, additional, Joynson, Jeff, additional, Leader, Brandon T., additional, Van Voorhis, Wesley C., additional, and Domingo, Gonzalo J., additional

Published
2017
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214. 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

215. Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

Author

Ojo, Kayode K., Ranade, Ranae M., Zhang, Zhongsheng, Dranow, David M., Myers, Janette B., Choi, Ryan, Hewitt, Steve Nakazawa, Edwards, Thomas E., Davies, Douglas R., Lorimer, Donald, Boyle, Stephen M., Barrett, Lynn K., Buckner, Frederick S., Fan, Erkang, Van Voorhis, Wesley C., Ojo, Kayode K., Ranade, Ranae M., Zhang, Zhongsheng, Dranow, David M., Myers, Janette B., Choi, Ryan, Hewitt, Steve Nakazawa, Edwards, Thomas E., Davies, Douglas R., Lorimer, Donald, Boyle, Stephen M., Barrett, Lynn K., Buckner, Frederick S., Fan, Erkang, and Van Voorhis, Wesley C.

Abstract

We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment.

Published
2016
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216. 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

218. Correction: Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

Author

Ojo, Kayode K., primary, Ranade, Ranae M., additional, Zhang, Zhongsheng, additional, Dranow, David M., additional, Myers, Janette B., additional, Choi, Ryan, additional, Nakazawa Hewitt, Steve, additional, Edwards, Thomas E., additional, Davies, Douglas R., additional, Lorimer, Donald, additional, Boyle, Stephen M., additional, Barrett, Lynn K., additional, Buckner, Frederick S., additional, Fan, Erkang, additional, and Van Voorhis, Wesley C., additional

Published
2016
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219. Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

Author

Ojo, Kayode K., primary, Ranade, Ranae M., additional, Zhang, Zhongsheng, additional, Dranow, David M., additional, Myers, Janette B., additional, Choi, Ryan, additional, Nakazawa Hewitt, Steve, additional, Edwards, Thomas E., additional, Davies, Douglas R., additional, Lorimer, Donald, additional, Boyle, Stephen M., additional, Barrett, Lynn K., additional, Buckner, Frederick S., additional, Fan, Erkang, additional, and Van Voorhis, Wesley C., additional

Published
2016
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220. Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

Author

Vidadala, Rama Subba Rao, primary, Rivas, Kasey L., additional, Ojo, Kayode K., additional, Hulverson, Matthew A., additional, Zambriski, Jennifer A., additional, Bruzual, Igor, additional, Schultz, Tracey L., additional, Huang, Wenlin, additional, Zhang, Zhongsheng, additional, Scheele, Suzanne, additional, DeRocher, Amy E., additional, Choi, Ryan, additional, Barrett, Lynn K., additional, Siddaramaiah, Latha Kallur, additional, Hol, Wim G. J., additional, Fan, Erkang, additional, Merritt, Ethan A., additional, Parsons, Marilyn, additional, Freiberg, Gail, additional, Marsh, Kennan, additional, Kempf, Dale J., additional, Carruthers, Vern B., additional, Isoherranen, Nina, additional, Doggett, J. Stone, additional, Van Voorhis, Wesley C., additional, and Maly, Dustin J., additional

Published
2016
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221. Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds

Author

Crowther, Gregory J., primary, Hillesland, Heidi K., additional, Keyloun, Katelyn R., additional, Reid, Molly C., additional, Lafuente-Monasterio, Maria Jose, additional, Ghidelli-Disse, Sonja, additional, Leonard, Stephen E., additional, He, Panqing, additional, Jones, Jackson C., additional, Krahn, Mallory M., additional, Mo, Jack S., additional, Dasari, Kartheek S., additional, Fox, Anna M. W., additional, Boesche, Markus, additional, El Bakkouri, Majida, additional, Rivas, Kasey L., additional, Leroy, Didier, additional, Hui, Raymond, additional, Drewes, Gerard, additional, Maly, Dustin J., additional, Van Voorhis, Wesley C., additional, and Ojo, Kayode K., additional

Published
2016
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222. Structure and analysis of nucleoside diphosphate kinase from Borrelia burgdorferi prepared in a transition‐state complex with ADP and vanadate moieties.

Author

Dumais, Mitchell, Davies, Douglas R., Lin, Tao, Staker, Bart L., Myler, Peter J., and Van Voorhis, Wesley C.

Subjects
NUCLEOSIDE diphosphate kinases, BORRELIA burgdorferi, ADENOSINE diphosphate
Abstract

Nucleoside diphosphate kinases (NDKs) are implicated in a wide variety of cellular functions owing to their enzymatic conversion of NDP to NTP. NDK from Borrelia burgdorferi (BbNDK) was selected for functional and structural analysis to determine whether its activity is required for infection and to assess its potential for therapeutic inhibition. The Seattle Structural Genomics Center for Infectious Diseases (SSGCID) expressed recombinant BbNDK protein. The protein was crystallized and structures were solved of both the apoenzyme and a liganded form with ADP and vanadate ligands. This provided two structures and allowed the elucidation of changes between the apo and ligand‐bound enzymes. Infectivity studies with ndk transposon mutants demonstrated that NDK function was important for establishing a robust infection in mice, and provided a rationale for therapeutic targeting of BbNDK. The protein structure was compared with other NDK structures found in the Protein Data Bank and was found to have similar primary, secondary, tertiary and quaternary structures, with conserved residues acting as the catalytic pocket, primarily using His132 as the phosphohistidine‐transfer residue. Vanadate and ADP complexes model the transition state of this phosphoryl‐transfer reaction, demonstrating that the pocket closes when bound to ADP, while allowing the addition or removal of a γ‐phosphate. This analysis provides a framework for the design of potential therapeutics targeting BbNDK inhibition. [ABSTRACT FROM AUTHOR]

Published
2018
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224. Appraisal of Fungus-Derived Xanthoquinodins as Broad-Spectrum Anti-Infectives Targeting Phylogenetically Diverse Human Pathogens

Author

Lee, Jin Woo, Collins, Jennifer E., Hulverson, Matthew A., Aguila, Laarni Kendra T., Kim, Caroline M., Wendt, Karen L., Chakrabarti, Debopam, Ojo, Kayode K., Wood, Gwendolyn E., Van Voorhis, Wesley C., and Cichewicz, Robert H.

Abstract

Xanthoquinodins make up a distinctive class of xanthone-anthraquinone heterodimers reported as secondary metabolites from several fungal species. Through a collaborative multi-institutional screening program, a fungal extract prepared from a Trichocladiumsp. was identified that exhibited strong inhibitory effects against several human pathogens (Mycoplasma genitalium, Plasmodium falciparum, Cryptosporidium parvum, and Trichomonas vaginalis). This report focuses on one of the unique samples that exhibited a desirable combination of biological effects: namely, it inhibited all four test pathogens and demonstrated low levels of toxicity toward HepG2 (human liver) cells. Fractionation and purification of the bioactive components and their congeners led to the identification of six new compounds [xanthoquinodins NPDG A1-A5 (1–5) and B1 (6)] as well as several previously reported natural products (7–14). The chemical structures of 1–14were determined based on interpretation of their 1D and 2D NMR, HRESIMS, and electronic circular dichroism (ECD) data. Biological testing of the purified metabolites revealed that they possessed widely varying levels of inhibitory activity against a panel of human pathogens. Xanthoquinodins A1 (7) and A2 (8) exhibited the most promising broad-spectrum inhibitory effects against M. genitalium(EC50values: 0.13 and 0.12 μM, respectively), C. parvum(EC50values: 5.2 and 3.5 μM, respectively), T. vaginalis(EC50values: 3.9 and 6.8 μM, respectively), and P. falciparum(EC50values: 0.29 and 0.50 μM, respectively) with no cytotoxicity detected at the highest concentration tested (HepG2 EC50> 25 μM).

Published
2024
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225. SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1

Author

Huang, Wenlin, primary, Ojo, Kayode K., additional, Zhang, Zhongsheng, additional, Rivas, Kasey, additional, Vidadala, Rama Subba Rao, additional, Scheele, Suzanne, additional, DeRocher, Amy E., additional, Choi, Ryan, additional, Hulverson, Matthew A., additional, Barrett, Lynn K., additional, Bruzual, Igor, additional, Siddaramaiah, Latha Kallur, additional, Kerchner, Keshia M., additional, Kurnick, Matthew D., additional, Freiberg, Gail M., additional, Kempf, Dale, additional, Hol, Wim G. J., additional, Merritt, Ethan A., additional, Neckermann, Georg, additional, de Hostos, Eugenio L., additional, Isoherranen, Nina, additional, Maly, Dustin J., additional, Parsons, Marilyn, additional, Doggett, J. Stone, additional, Van Voorhis, Wesley C., additional, and Fan, Erkang, additional

Published
2015
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226. In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum

Author

Winzer, Pablo, primary, Müller, Joachim, additional, Aguado-Martínez, Adriana, additional, Rahman, Mahbubur, additional, Balmer, Vreni, additional, Manser, Vera, additional, Ortega-Mora, Luis Miguel, additional, Ojo, Kayode K., additional, Fan, Erkang, additional, Maly, Dustin J., additional, Van Voorhis, Wesley C., additional, and Hemphill, Andrew, additional

Published
2015
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230. Structure of a CutA1 divalent-cation tolerance protein fromCryptosporidium parvum, the protozoal parasite responsible for cryptosporidiosis

Author

Buchko, Garry W., primary, Abendroth, Jan, additional, Clifton, Matthew C., additional, Robinson, Howard, additional, Zhang, Yanfeng, additional, Hewitt, Stephen N., additional, Staker, Bart L., additional, Edwards, Thomas E., additional, Van Voorhis, Wesley C., additional, and Myler, Peter J., additional

Published
2015
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231. Crystal structures of Mycobacterial MeaB and MMAA-like GTPases

Author

Edwards, Thomas E., primary, Baugh, Loren, additional, Bullen, Jameson, additional, Baydo, Ruth O., additional, Witte, Pam, additional, Thompkins, Kaitlin, additional, Phan, Isabelle Q. H., additional, Abendroth, Jan, additional, Clifton, Matthew C., additional, Sankaran, Banumathi, additional, Van Voorhis, Wesley C., additional, Myler, Peter J., additional, Staker, Bart L., additional, Grundner, Christoph, additional, and Lorimer, Donald D., additional

Published
2015
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232. Increasing the structural coverage of tuberculosis drug targets

Author

Baugh, Loren, primary, Phan, Isabelle, additional, Begley, Darren W., additional, Clifton, Matthew C., additional, Armour, Brianna, additional, Dranow, David M., additional, Taylor, Brandy M., additional, Muruthi, Marvin M., additional, Abendroth, Jan, additional, Fairman, James W., additional, Fox, David, additional, Dieterich, Shellie H., additional, Staker, Bart L., additional, Gardberg, Anna S., additional, Choi, Ryan, additional, Hewitt, Stephen N., additional, Napuli, Alberto J., additional, Myers, Janette, additional, Barrett, Lynn K., additional, Zhang, Yang, additional, Ferrell, Micah, additional, Mundt, Elizabeth, additional, Thompkins, Katie, additional, Tran, Ngoc, additional, Lyons-Abbott, Sally, additional, Abramov, Ariel, additional, Sekar, Aarthi, additional, Serbzhinskiy, Dmitri, additional, Lorimer, Don, additional, Buchko, Garry W., additional, Stacy, Robin, additional, Stewart, Lance J., additional, Edwards, Thomas E., additional, Van Voorhis, Wesley C., additional, and Myler, Peter J., additional

Published
2015
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233. Use of thermal melt curves to assess the quality of enzyme preparations1

Author

Crowther, Gregory J., He, Panqing, Rodenbough, Philip P., Thomas, Andrew P., Kovzun, Kuzma V., Leibly, David J., Bhandari, Janhavi, Castaneda, Lisa J., Hol, Wim G. J., Gelb, Michael H., Napuli, Alberto J., and Van Voorhis, Wesley C.

Subjects
Plasmodium, Protein Denaturation, Xanthine Oxidase, Hot Temperature, Reverse Transcriptase Polymerase Chain Reaction, Entamoeba histolytica, Sodium Dodecyl Sulfate, Article, Phase Transition, Enzymes, Cysteine Proteases, Animals, Cattle, Enzyme Assays, Fluorescent Dyes
Abstract

This study sought to determine whether the quality of enzyme preparations can be determined from their melting curves, which may easily be obtained using a fluorescent probe and a standard reverse transcription-polymerase chain reaction (RT-PCR) machine. Thermal melt data on 31 recombinant enzymes from Plasmodium parasites were acquired by incrementally heating them to 90 degrees C and measuring unfolding with a fluorescent dye. Activity assays specific to each enzyme were also performed. Four of the enzymes were denatured to varying degrees with heat and sodium dodecyl sulfate (SDS) prior to the thermal melt and activity assays. In general, melting curve quality was correlated with enzyme activity; enzymes with high-quality curves were found almost uniformly to be active, whereas those with lower quality curves were more varied in their catalytic performance. Inspection of melting curves of bovine xanthine oxidase and Entamoeba histolytica cysteine protease 1 allowed active stocks to be distinguished from inactive stocks, implying that a relationship between melting curve quality and activity persists over a wide range of experimental conditions and species. Our data suggest that melting curves can help to distinguish properly folded proteins from denatured ones and, therefore, may be useful in selecting stocks for further study and in optimizing purification procedures for specific proteins.

Published
2009

235. Solution NMR structures of oxidized and reduced <italic>Ehrlichia chaffeensis</italic> thioredoxin: NMR‐invisible structure owing to backbone dynamics.

Author

Buchko, Garry W., Hewitt, Stephen N., Van Voorhis, Wesley C., and Myler, Peter J.

Subjects
THIOREDOXIN, NUCLEAR magnetic resonance, EHRLICHIOSIS
Abstract

Thioredoxins are small ubiquitous proteins that participate in a diverse variety of redox reactions via the reversible oxidation of two cysteine thiol groups in a structurally conserved active site. Here, the NMR solution structures of a reduced and oxidized thioredoxin from Ehrlichia chaffeensis (Ec‐Trx, ECH_0218), the etiological agent responsible for human monocytic ehrlichiosis, are described. The overall topology of the calculated structures is similar in both redox states and is similar to those of other thioredoxins: a five‐stranded, mixed β‐sheet (β1–β3–β2–β4–β5) surrounded by four α‐helices. Unlike other thioredoxins studied by NMR in both redox states, the 1H–15N HSQC spectrum of reduced Ec‐Trx was missing eight additional amide cross peaks relative to the spectrum of oxidized Ec‐Trx. These missing amides correspond to residues Cys35–Glu39 in the active‐site‐containing helix (α2) and Ser72–Ile75 in a loop near the active site, and suggest a change in backbone dynamics on the millisecond‐to‐microsecond timescale associated with the breakage of an intramolecular Cys32–Cys35 disulfide bond in a thioredoxin. A consequence of the missing amide resonances is the absence of observable or unambiguous NOEs to provide the distance restraints necessary to define the N‐terminal end of the α‐helix containing the CPGC active site in the reduced state. This region adopts a well defined α‐helical structure in other reported reduced thioredoxin structures, is mostly helical in oxidized Ec‐Trx and CD studies of Ec‐Trx in both redox states suggests there is no significant difference in the secondary structure of the protein. The NMR solution structure of reduced Ec‐Trx illustrates that the absence of canonical structure in a region of a protein may be owing to unfavorable dynamics prohibiting NOE observations or unambiguous NOE assignments. [ABSTRACT FROM AUTHOR]

Published
2018
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236. Extended-spectrum antiprotozoal bumped kinase inhibitors: A review.

Author

Van Voorhis, Wesley C., Doggett, J. Stone, Parsons, Marilyn, Hulverson, Matthew A., Choi, Ryan, Arnold, Samuel L.M., Riggs, Michael W., Hemphill, Andrew, Howe, Daniel K., Mealey, Robert H., Lau, Audrey O.T., Merritt, Ethan A., Maly, Dustin J., Fan, Erkang, and Ojo, Kayode K.

Subjects
*KINASE inhibitors, *NILOTINIB, *PROTEIN kinase B, *APICOMPLEXA, *PHARMACOKINETICS, *PHOSPHORYLATION
Abstract

Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro , and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors. [ABSTRACT FROM AUTHOR]

Published
2017
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237. Necessity of Bumped Kinase Inhibitor Gastrointestinal Exposure in Treating Cryptosporidium Infection.

Author

Arnold, Samuel L. M., Choi, Ryan, Hulverson, Matthew A., Schaefer, Deborah A., Vinayak, Sumiti, Vidadala, Rama S. R., McCloskey, Molly C., Whitman, Grant R., Huang, Wenlin, Barrett, Lynn K., Ojo, Kayode K., Fan, Erkang, Maly, Dustin J., Riggs, Michael W., Striepen, Boris, and Van Voorhis, Wesley C.

Subjects
CRYPTOSPORIDIIDAE, CRYPTOSPORIDIUM, MEDICAL microbiology, ETIOLOGY of diseases, KINASE inhibitors, ENZYME inhibitors, ANIMAL experimentation, BIOLOGICAL models, CRYPTOSPORIDIOSIS, DOSE-effect relationship in pharmacology, GASTROINTESTINAL system, HETEROCYCLIC compounds, HYDROCARBONS, MATHEMATICAL models, MICE, PIPERIDINE, THEORY, PROTEIN kinase inhibitors
Abstract

There is a substantial need for novel therapeutics to combat the widespread impact caused by Crytosporidium infection. However, there is a lack of knowledge as to which drug pharmacokinetic (PK) characteristics are key to generate an in vivo response, specifically whether systemic drug exposure is crucial for in vivo efficacy. To identify which PK properties are correlated with in vivo efficacy, we generated physiologically based PK models to simulate systemic and gastrointestinal drug concentrations for a series of bumped kinase inhibitors (BKIs) that have nearly identical in vitro potency against Cryptosporidium but display divergent PK properties. When BKI concentrations were used to predict in vivo efficacy with a neonatal model of Cryptosporidium infection, these concentrations in the large intestine were the sole predictors of the observed in vivo efficacy. The significance of large intestinal BKI exposure for predicting in vivo efficacy was further supported with an adult mouse model of Cryptosporidium infection. This study suggests that drug exposure in the large intestine is essential for generating a superior in vivo response, and that physiologically based PK models can assist in the prioritization of leading preclinical drug candidates for in vivo testing. [ABSTRACT FROM AUTHOR]

Published
2017
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238. Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.

Author

Hulverson, Matthew A., Vinayak, Sumiti, Choi, Ryan, Schaefer, Deborah A., Castellanos-Gonzalez, Alejandro, Vidadala, Rama S. R., Brooks, Carrie F., Herbert, Gillian T., Betzer, Dana P., Whitman, Grant R., Sparks, Hayley N., Arnold, Samuel L. M., Rivas, Kasey L., Barrett, Lynn K., White Jr., A. Clinton, Maly, Dustin J., Riggs, Michael W., Striepen, Boris, Van Voorhis, Wesley C., and Ojo, Kayode K.

Subjects
CRYPTOSPORIDIOSIS, KINASE inhibitors, PROTEIN kinases, CARDIOTOXICITY, LUMINESCENCE, MAMMALIAN cell cycle, ANIMALS, BIOLOGICAL models, CRYPTOSPORIDIUM, DIARRHEA, MICE, ORAL drug administration, ANTIPROTOZOAL agents, PROTEIN kinase inhibitors
Abstract

Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) are leading candidates for treatment of cryptosporidiosis-associated diarrhea. Potential cardiotoxicity related to anti-human ether-à-go-go potassium channel (hERG) activity of the first-generation anti-Cryptosporidium BKIs triggered further testing for efficacy. A luminescence assay adapted for high-throughput screening was used to measure inhibitory activities of BKIs against C. parvum in vitro. Furthermore, neonatal and interferon γ knockout mouse models of C. parvum infection identified BKIs with in vivo activity. Additional iterative experiments for optimum dosing and selecting BKIs with minimum levels of hERG activity and frequencies of other safety liabilities included those that investigated mammalian cell cytotoxicity, C. parvum proliferation inhibition in vitro, anti-human Src inhibition, hERG activity, in vivo pharmacokinetic data, and efficacy in other mouse models. Findings of this study suggest that fecal concentrations greater than parasite inhibitory concentrations correlate best with effective therapy in the mouse model of cryptosporidiosis, but a more refined model for efficacy is needed. [ABSTRACT FROM AUTHOR]

Published
2017
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239. Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail.

Author

Addetia, Amin, Park, Young-Jun, Starr, Tyler, Greaney, Allison J., Sprouse, Kaitlin R., Bowen, John E., Tiles, Sasha W., Van Voorhis, Wesley C., Bloom, Jesse D., Corti, Davide, Walls, Alexandra C., and Veesler, David

Abstract

Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-COV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the AZD1061 (COV2-2130) mAb. Here, we show that this mutation remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution. [Display omitted] • The SARS-CoV-2 spike E406W mutation remodels receptor-binding motif • E406W-induced structural changes impact the epitopes of three monoclonal antibodies • The remodeled E406W spike retains some, but not all, key contacts with the receptor, ACE2 • Vaccine-elicited sera have reduced potency against E406W spike pseudovirus Addetia et al. demonstrate that introduction of the E406W mutation in the SARS-CoV-2 spike protein causes widespread structural changes in the receptor-binding motif. These changes hinder the ability of three therapeutic antibodies to effectively bind the mutated spike protein. [ABSTRACT FROM AUTHOR]

Published
2023
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244. Safety and Comparability of Controlled Human Plasmodium falciparum Infection by Mosquito Bite in Malaria-Naïve Subjects at a New Facility for Sporozoite Challenge

Author

Talley, Angela K., primary, Healy, Sara A., additional, Finney, Olivia C., additional, Murphy, Sean C., additional, Kublin, James, additional, Salas, Carola J., additional, Lundebjerg, Susan, additional, Gilbert, Peter, additional, Van Voorhis, Wesley C., additional, Whisler, John, additional, Wang, Ruobing, additional, Ockenhouse, Chris F., additional, Heppner, D. Gray, additional, Kappe, Stefan H., additional, and Duffy, Patrick E., additional

Published
2014
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247. Neospora caninum Calcium-Dependent Protein Kinase 1 Is an Effective Drug Target for Neosporosis Therapy

Author

Ojo, Kayode K., primary, Reid, Molly C., additional, Kallur Siddaramaiah, Latha, additional, Müller, Joachim, additional, Winzer, Pablo, additional, Zhang, Zhongsheng, additional, Keyloun, Katelyn R., additional, Vidadala, Rama Subba Rao, additional, Merritt, Ethan A., additional, Hol, Wim G. J., additional, Maly, Dustin J., additional, Fan, Erkang, additional, Van Voorhis, Wesley C., additional, and Hemphill, Andrew, additional

Published
2014
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248. Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes

Author

Vidadala, Rama Subba Rao, primary, Ojo, Kayode K., additional, Johnson, Steven M., additional, Zhang, Zhongsheng, additional, Leonard, Stephen E., additional, Mitra, Arinjay, additional, Choi, Ryan, additional, Reid, Molly C., additional, Keyloun, Katelyn R., additional, Fox, Anna M.W., additional, Kennedy, Mark, additional, Silver-Brace, Tiffany, additional, Hume, Jen C.C., additional, Kappe, Stefan, additional, Verlinde, Christophe L.M.J., additional, Fan, Erkang, additional, Merritt, Ethan A., additional, Van Voorhis, Wesley C., additional, and Maly, Dustin J., additional

Published
2014
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249. Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors

Author

Ojo, Kayode K, Pfander, Claudia, Mueller, Natascha R, Burstroem, Charlotte, Larson, Eric T, Bryan, Cassie M, Fox, Anna M W, Reid, Molly C, Johnson, Steven M, Murphy, Ryan C, Kennedy, Mark, Mann, Henning, Leibly, David J, Hewitt, Stephen N, Verlinde, Christophe L M J, Kappe, Stefan, Merritt, Ethan A, Maly, Dustin J, Billker, Oliver, Van Voorhis, Wesley C, Ojo, Kayode K, Pfander, Claudia, Mueller, Natascha R, Burstroem, Charlotte, Larson, Eric T, Bryan, Cassie M, Fox, Anna M W, Reid, Molly C, Johnson, Steven M, Murphy, Ryan C, Kennedy, Mark, Mann, Henning, Leibly, David J, Hewitt, Stephen N, Verlinde, Christophe L M J, Kappe, Stefan, Merritt, Ethan A, Maly, Dustin J, Billker, Oliver, and Van Voorhis, Wesley C

Abstract

Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1-treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.

Published
2012
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250. Chemical genetics of Plasmodium falciparum.

Author

Guiguemde, W Armand, 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, El Mazouni, Farah, 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, Guy, R Kiplin, Guiguemde, W Armand, 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, El Mazouni, Farah, 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

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

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