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Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused...

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Autores principales: Machutta, Carl A., Kollmann, Christopher S., Lind, Kenneth E., Bai, Xiaopeng, Chan, Pan F., Huang, Jianzhong, Ballell, Lluis, Belyanskaya, Svetlana, Besra, Gurdyal S., Barros-Aguirre, David, Bates, Robert H., Centrella, Paolo A., Chang, Sandy S., Chai, Jing, Choudhry, Anthony E., Coffin, Aaron, Davie, Christopher P., Deng, Hongfeng, Deng, Jianghe, Ding, Yun, Dodson, Jason W., Fosbenner, David T., Gao, Enoch N., Graham, Taylor L., Graybill, Todd L., Ingraham, Karen, Johnson, Walter P., King, Bryan W., Kwiatkowski, Christopher R., Lelièvre, Joël, Li, Yue, Liu, Xiaorong, Lu, Quinn, Lehr, Ruth, Mendoza-Losana, Alfonso, Martin, John, McCloskey, Lynn, McCormick, Patti, O’Keefe, Heather P., O’Keeffe, Thomas, Pao, Christina, Phelps, Christopher B., Qi, Hongwei, Rafferty, Keith, Scavello, Genaro S., Steiginga, Matt S., Sundersingh, Flora S., Sweitzer, Sharon M., Szewczuk, Lawrence M., Taylor, Amy, Toh, May Fern, Wang, Juan, Wang, Minghui, Wilkins, Devan J., Xia, Bing, Yao, Gang, Zhang, Jean, Zhou, Jingye, Donahue, Christine P., Messer, Jeffrey A., Holmes, David, Arico-Muendel, Christopher C., Pope, Andrew J., Gross, Jeffrey W., Evindar, Ghotas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520047/
https://www.ncbi.nlm.nih.gov/pubmed/28714473
http://dx.doi.org/10.1038/ncomms16081
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author Machutta, Carl A.
Kollmann, Christopher S.
Lind, Kenneth E.
Bai, Xiaopeng
Chan, Pan F.
Huang, Jianzhong
Ballell, Lluis
Belyanskaya, Svetlana
Besra, Gurdyal S.
Barros-Aguirre, David
Bates, Robert H.
Centrella, Paolo A.
Chang, Sandy S.
Chai, Jing
Choudhry, Anthony E.
Coffin, Aaron
Davie, Christopher P.
Deng, Hongfeng
Deng, Jianghe
Ding, Yun
Dodson, Jason W.
Fosbenner, David T.
Gao, Enoch N.
Graham, Taylor L.
Graybill, Todd L.
Ingraham, Karen
Johnson, Walter P.
King, Bryan W.
Kwiatkowski, Christopher R.
Lelièvre, Joël
Li, Yue
Liu, Xiaorong
Lu, Quinn
Lehr, Ruth
Mendoza-Losana, Alfonso
Martin, John
McCloskey, Lynn
McCormick, Patti
O’Keefe, Heather P.
O’Keeffe, Thomas
Pao, Christina
Phelps, Christopher B.
Qi, Hongwei
Rafferty, Keith
Scavello, Genaro S.
Steiginga, Matt S.
Sundersingh, Flora S.
Sweitzer, Sharon M.
Szewczuk, Lawrence M.
Taylor, Amy
Toh, May Fern
Wang, Juan
Wang, Minghui
Wilkins, Devan J.
Xia, Bing
Yao, Gang
Zhang, Jean
Zhou, Jingye
Donahue, Christine P.
Messer, Jeffrey A.
Holmes, David
Arico-Muendel, Christopher C.
Pope, Andrew J.
Gross, Jeffrey W.
Evindar, Ghotas
author_facet Machutta, Carl A.
Kollmann, Christopher S.
Lind, Kenneth E.
Bai, Xiaopeng
Chan, Pan F.
Huang, Jianzhong
Ballell, Lluis
Belyanskaya, Svetlana
Besra, Gurdyal S.
Barros-Aguirre, David
Bates, Robert H.
Centrella, Paolo A.
Chang, Sandy S.
Chai, Jing
Choudhry, Anthony E.
Coffin, Aaron
Davie, Christopher P.
Deng, Hongfeng
Deng, Jianghe
Ding, Yun
Dodson, Jason W.
Fosbenner, David T.
Gao, Enoch N.
Graham, Taylor L.
Graybill, Todd L.
Ingraham, Karen
Johnson, Walter P.
King, Bryan W.
Kwiatkowski, Christopher R.
Lelièvre, Joël
Li, Yue
Liu, Xiaorong
Lu, Quinn
Lehr, Ruth
Mendoza-Losana, Alfonso
Martin, John
McCloskey, Lynn
McCormick, Patti
O’Keefe, Heather P.
O’Keeffe, Thomas
Pao, Christina
Phelps, Christopher B.
Qi, Hongwei
Rafferty, Keith
Scavello, Genaro S.
Steiginga, Matt S.
Sundersingh, Flora S.
Sweitzer, Sharon M.
Szewczuk, Lawrence M.
Taylor, Amy
Toh, May Fern
Wang, Juan
Wang, Minghui
Wilkins, Devan J.
Xia, Bing
Yao, Gang
Zhang, Jean
Zhou, Jingye
Donahue, Christine P.
Messer, Jeffrey A.
Holmes, David
Arico-Muendel, Christopher C.
Pope, Andrew J.
Gross, Jeffrey W.
Evindar, Ghotas
author_sort Machutta, Carl A.
collection PubMed
description The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.
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spelling pubmed-55200472017-07-28 Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening Machutta, Carl A. Kollmann, Christopher S. Lind, Kenneth E. Bai, Xiaopeng Chan, Pan F. Huang, Jianzhong Ballell, Lluis Belyanskaya, Svetlana Besra, Gurdyal S. Barros-Aguirre, David Bates, Robert H. Centrella, Paolo A. Chang, Sandy S. Chai, Jing Choudhry, Anthony E. Coffin, Aaron Davie, Christopher P. Deng, Hongfeng Deng, Jianghe Ding, Yun Dodson, Jason W. Fosbenner, David T. Gao, Enoch N. Graham, Taylor L. Graybill, Todd L. Ingraham, Karen Johnson, Walter P. King, Bryan W. Kwiatkowski, Christopher R. Lelièvre, Joël Li, Yue Liu, Xiaorong Lu, Quinn Lehr, Ruth Mendoza-Losana, Alfonso Martin, John McCloskey, Lynn McCormick, Patti O’Keefe, Heather P. O’Keeffe, Thomas Pao, Christina Phelps, Christopher B. Qi, Hongwei Rafferty, Keith Scavello, Genaro S. Steiginga, Matt S. Sundersingh, Flora S. Sweitzer, Sharon M. Szewczuk, Lawrence M. Taylor, Amy Toh, May Fern Wang, Juan Wang, Minghui Wilkins, Devan J. Xia, Bing Yao, Gang Zhang, Jean Zhou, Jingye Donahue, Christine P. Messer, Jeffrey A. Holmes, David Arico-Muendel, Christopher C. Pope, Andrew J. Gross, Jeffrey W. Evindar, Ghotas Nat Commun Article The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery. Nature Publishing Group 2017-07-17 /pmc/articles/PMC5520047/ /pubmed/28714473 http://dx.doi.org/10.1038/ncomms16081 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Machutta, Carl A.
Kollmann, Christopher S.
Lind, Kenneth E.
Bai, Xiaopeng
Chan, Pan F.
Huang, Jianzhong
Ballell, Lluis
Belyanskaya, Svetlana
Besra, Gurdyal S.
Barros-Aguirre, David
Bates, Robert H.
Centrella, Paolo A.
Chang, Sandy S.
Chai, Jing
Choudhry, Anthony E.
Coffin, Aaron
Davie, Christopher P.
Deng, Hongfeng
Deng, Jianghe
Ding, Yun
Dodson, Jason W.
Fosbenner, David T.
Gao, Enoch N.
Graham, Taylor L.
Graybill, Todd L.
Ingraham, Karen
Johnson, Walter P.
King, Bryan W.
Kwiatkowski, Christopher R.
Lelièvre, Joël
Li, Yue
Liu, Xiaorong
Lu, Quinn
Lehr, Ruth
Mendoza-Losana, Alfonso
Martin, John
McCloskey, Lynn
McCormick, Patti
O’Keefe, Heather P.
O’Keeffe, Thomas
Pao, Christina
Phelps, Christopher B.
Qi, Hongwei
Rafferty, Keith
Scavello, Genaro S.
Steiginga, Matt S.
Sundersingh, Flora S.
Sweitzer, Sharon M.
Szewczuk, Lawrence M.
Taylor, Amy
Toh, May Fern
Wang, Juan
Wang, Minghui
Wilkins, Devan J.
Xia, Bing
Yao, Gang
Zhang, Jean
Zhou, Jingye
Donahue, Christine P.
Messer, Jeffrey A.
Holmes, David
Arico-Muendel, Christopher C.
Pope, Andrew J.
Gross, Jeffrey W.
Evindar, Ghotas
Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
title Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
title_full Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
title_fullStr Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
title_full_unstemmed Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
title_short Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening
title_sort prioritizing multiple therapeutic targets in parallel using automated dna-encoded library screening
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520047/
https://www.ncbi.nlm.nih.gov/pubmed/28714473
http://dx.doi.org/10.1038/ncomms16081
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