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The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis

The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has becom...

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Autores principales: Janes, Jeff, Young, Megan E., Chen, Emily, Rogers, Nicole H., Burgstaller-Muehlbacher, Sebastian, Hughes, Laura D., Love, Melissa S., Hull, Mitchell V., Kuhen, Kelli L., Woods, Ashley K., Joseph, Sean B., Petrassi, H. Michael, McNamara, Case W., Tremblay, Matthew S., Su, Andrew I., Schultz, Peter G., Chatterjee, Arnab K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196526/
https://www.ncbi.nlm.nih.gov/pubmed/30282735
http://dx.doi.org/10.1073/pnas.1810137115
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author Janes, Jeff
Young, Megan E.
Chen, Emily
Rogers, Nicole H.
Burgstaller-Muehlbacher, Sebastian
Hughes, Laura D.
Love, Melissa S.
Hull, Mitchell V.
Kuhen, Kelli L.
Woods, Ashley K.
Joseph, Sean B.
Petrassi, H. Michael
McNamara, Case W.
Tremblay, Matthew S.
Su, Andrew I.
Schultz, Peter G.
Chatterjee, Arnab K.
author_facet Janes, Jeff
Young, Megan E.
Chen, Emily
Rogers, Nicole H.
Burgstaller-Muehlbacher, Sebastian
Hughes, Laura D.
Love, Melissa S.
Hull, Mitchell V.
Kuhen, Kelli L.
Woods, Ashley K.
Joseph, Sean B.
Petrassi, H. Michael
McNamara, Case W.
Tremblay, Matthew S.
Su, Andrew I.
Schultz, Peter G.
Chatterjee, Arnab K.
author_sort Janes, Jeff
collection PubMed
description The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.
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spelling pubmed-61965262018-10-23 The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis Janes, Jeff Young, Megan E. Chen, Emily Rogers, Nicole H. Burgstaller-Muehlbacher, Sebastian Hughes, Laura D. Love, Melissa S. Hull, Mitchell V. Kuhen, Kelli L. Woods, Ashley K. Joseph, Sean B. Petrassi, H. Michael McNamara, Case W. Tremblay, Matthew S. Su, Andrew I. Schultz, Peter G. Chatterjee, Arnab K. Proc Natl Acad Sci U S A Biological Sciences The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of “drug repurposing” has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection. National Academy of Sciences 2018-10-16 2018-10-03 /pmc/articles/PMC6196526/ /pubmed/30282735 http://dx.doi.org/10.1073/pnas.1810137115 Text en Copyright © 2018 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Janes, Jeff
Young, Megan E.
Chen, Emily
Rogers, Nicole H.
Burgstaller-Muehlbacher, Sebastian
Hughes, Laura D.
Love, Melissa S.
Hull, Mitchell V.
Kuhen, Kelli L.
Woods, Ashley K.
Joseph, Sean B.
Petrassi, H. Michael
McNamara, Case W.
Tremblay, Matthew S.
Su, Andrew I.
Schultz, Peter G.
Chatterjee, Arnab K.
The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
title The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
title_full The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
title_fullStr The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
title_full_unstemmed The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
title_short The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
title_sort reframe library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196526/
https://www.ncbi.nlm.nih.gov/pubmed/30282735
http://dx.doi.org/10.1073/pnas.1810137115
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