Open source drug discovery: Highly potent antimalarial compounds derived from the tres cantos arylpyrroles

Alice E. Williamson; Paul M. Ylioja; Murray N. Robertson; Vicky Avery; Jonathan B. Baell; Harikrishna Batchu; Sanjay Batra; Jeremy N. Burrows; Soumya Bhattacharyya; Felix Calderon; Susan A. Charman; Julie Clark; Benigno Crespo; Matin Dean; Stefan L. Debbert; Michael Delves; Adelaide S.M. Dennis; Frederik Deroose; Sandra Duffy; Sabine Fletcher; Guri Giaever; Irene Hallyburton; Francisco Javier Gamo; Marinella Gebbia; R. Kiplin Guy; Zoe Hungerford; Kiaran Kirk; Maria J. Lafuente-Monasterio; Anna Lee; Stephan Meister; Corey Nislow; John P. Overington; George Papadatos; Luc Patiny; James Pham; Stuart A. Ralph; Andrea Ruecker; Eileen Ryan; Christopher Southan; Kumkum Srivastava; Chris Swain; Matthew J. Tarnowski; Patrick Thomson; Peter Turner; Iain M. Wallace; Timothy N.C. Wells; Karen White; Laura White; Paul Willis; Elizabeth A. Winzeler; Sergio Wittlin; Matthew H. Todd; Yevgeniya Antonova-Koch

doi:10.1021/acscentsci.6b00086

Open source drug discovery: Highly potent antimalarial compounds derived from the tres cantos arylpyrroles

Alice E. Williamson, Paul M. Ylioja, Murray N. Robertson, Vicky Avery, Jonathan B. Baell, Harikrishna Batchu, Sanjay Batra, Jeremy N. Burrows, Soumya Bhattacharyya, Felix Calderon, Susan A. Charman, Julie Clark, Benigno Crespo, Matin Dean, Stefan L. Debbert, Michael Delves, Adelaide S.M. Dennis, Frederik Deroose, Sandra Duffy, Sabine FletcherGuri Giaever, Irene Hallyburton, Francisco Javier Gamo, Marinella Gebbia, R. Kiplin Guy, Zoe Hungerford, Kiaran Kirk, Maria J. Lafuente-Monasterio, Anna Lee, Stephan Meister, Corey Nislow, John P. Overington, George Papadatos, Luc Patiny, James Pham, Stuart A. Ralph, Andrea Ruecker, Eileen Ryan, Christopher Southan, Kumkum Srivastava, Chris Swain, Matthew J. Tarnowski, Patrick Thomson, Peter Turner, Iain M. Wallace, Timothy N.C. Wells, Karen White, Laura White, Paul Willis, Elizabeth A. Winzeler, Sergio Wittlin, Matthew H. Todd, Yevgeniya Antonova-Koch

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

Abstract

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

Original language	English
Pages (from-to)	687-701
Number of pages	15
Journal	ACS Central Science
Volume	2
Issue number	10
DOIs	https://doi.org/10.1021/acscentsci.6b00086
State	Published - Oct 26 2016

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

Funding

Medicines for Malaria Venture (MMV), the Australian Research Council (LP120100552, LP120200557), the Australian National Health and Medical Research Council (Project Grant 1042272). G.P. and J.P.O. were supported by EMBL Member States and MMV. The characterization by NMR spectroscopy of compounds from Lawrence University was made possible by the National Science Foundation (CHE- 0923473). C.S. was supported by Wellcome Trust Biomedical Resources Grant 099156/Z/12/Z.

Funders	Funder number
Wellcome Trust Biomedical Resources	099156/Z/12/Z.
National Science Foundation Arctic Social Science Program	CHE- 0923473
National Science Foundation Arctic Social Science Program
European Molecular Biology Laboratory
Australian Research Council	LP120200557, LP120100552
Australian Research Council
Australian National Health and Medical Research Council	1042272
Australian National Health and Medical Research Council

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acscentsci.6b00086

Cite this

Williamson, A. E., Ylioja, P. M., Robertson, M. N., Avery, V., Baell, J. B., Batchu, H., Batra, S., Burrows, J. N., Bhattacharyya, S., Calderon, F., Charman, S. A., Clark, J., Crespo, B., Dean, M., Debbert, S. L., Delves, M., Dennis, A. S. M., Deroose, F., Duffy, S., ... Antonova-Koch, Y. (2016). Open source drug discovery: Highly potent antimalarial compounds derived from the tres cantos arylpyrroles. ACS Central Science, 2(10), 687-701. https://doi.org/10.1021/acscentsci.6b00086

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title = "Open source drug discovery: Highly potent antimalarial compounds derived from the tres cantos arylpyrroles",

abstract = "The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.",

author = "Williamson, {Alice E.} and Ylioja, {Paul M.} and Robertson, {Murray N.} and Vicky Avery and Baell, {Jonathan B.} and Harikrishna Batchu and Sanjay Batra and Burrows, {Jeremy N.} and Soumya Bhattacharyya and Felix Calderon and Charman, {Susan A.} and Julie Clark and Benigno Crespo and Matin Dean and Debbert, {Stefan L.} and Michael Delves and Dennis, {Adelaide S.M.} and Frederik Deroose and Sandra Duffy and Sabine Fletcher and Guri Giaever and Irene Hallyburton and Gamo, {Francisco Javier} and Marinella Gebbia and Guy, {R. Kiplin} and Zoe Hungerford and Kiaran Kirk and Lafuente-Monasterio, {Maria J.} and Anna Lee and Stephan Meister and Corey Nislow and Overington, {John P.} and George Papadatos and Luc Patiny and James Pham and Ralph, {Stuart A.} and Andrea Ruecker and Eileen Ryan and Christopher Southan and Kumkum Srivastava and Chris Swain and Tarnowski, {Matthew J.} and Patrick Thomson and Peter Turner and Wallace, {Iain M.} and Wells, {Timothy N.C.} and Karen White and Laura White and Paul Willis and Winzeler, {Elizabeth A.} and Sergio Wittlin and Todd, {Matthew H.} and Yevgeniya Antonova-Koch",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

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doi = "10.1021/acscentsci.6b00086",

language = "English",

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Williamson, AE, Ylioja, PM, Robertson, MN, Avery, V, Baell, JB, Batchu, H, Batra, S, Burrows, JN, Bhattacharyya, S, Calderon, F, Charman, SA, Clark, J, Crespo, B, Dean, M, Debbert, SL, Delves, M, Dennis, ASM, Deroose, F, Duffy, S, Fletcher, S, Giaever, G, Hallyburton, I, Gamo, FJ, Gebbia, M, Guy, RK, Hungerford, Z, Kirk, K, Lafuente-Monasterio, MJ, Lee, A, Meister, S, Nislow, C, Overington, JP, Papadatos, G, Patiny, L, Pham, J, Ralph, SA, Ruecker, A, Ryan, E, Southan, C, Srivastava, K, Swain, C, Tarnowski, MJ, Thomson, P, Turner, P, Wallace, IM, Wells, TNC, White, K, White, L, Willis, P, Winzeler, EA, Wittlin, S, Todd, MH & Antonova-Koch, Y 2016, 'Open source drug discovery: Highly potent antimalarial compounds derived from the tres cantos arylpyrroles', ACS Central Science, vol. 2, no. 10, pp. 687-701. https://doi.org/10.1021/acscentsci.6b00086

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AU - Williamson, Alice E.

AU - Ylioja, Paul M.

AU - Robertson, Murray N.

AU - Avery, Vicky

AU - Baell, Jonathan B.

AU - Batchu, Harikrishna

AU - Batra, Sanjay

AU - Burrows, Jeremy N.

AU - Bhattacharyya, Soumya

AU - Calderon, Felix

AU - Charman, Susan A.

AU - Clark, Julie

AU - Crespo, Benigno

AU - Dean, Matin

AU - Debbert, Stefan L.

AU - Delves, Michael

AU - Dennis, Adelaide S.M.

AU - Deroose, Frederik

AU - Duffy, Sandra

AU - Fletcher, Sabine

AU - Giaever, Guri

AU - Hallyburton, Irene

AU - Gamo, Francisco Javier

AU - Gebbia, Marinella

AU - Guy, R. Kiplin

AU - Hungerford, Zoe

AU - Kirk, Kiaran

AU - Lafuente-Monasterio, Maria J.

AU - Lee, Anna

AU - Meister, Stephan

AU - Nislow, Corey

AU - Overington, John P.

AU - Papadatos, George

AU - Patiny, Luc

AU - Pham, James

AU - Ralph, Stuart A.

AU - Ruecker, Andrea

AU - Ryan, Eileen

AU - Southan, Christopher

AU - Srivastava, Kumkum

AU - Swain, Chris

AU - Tarnowski, Matthew J.

AU - Thomson, Patrick

AU - Turner, Peter

AU - Wallace, Iain M.

AU - Wells, Timothy N.C.

AU - White, Karen

AU - White, Laura

AU - Willis, Paul

AU - Winzeler, Elizabeth A.

AU - Wittlin, Sergio

AU - Todd, Matthew H.

AU - Antonova-Koch, Yevgeniya

PY - 2016/10/26

Y1 - 2016/10/26

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AB - The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.

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Open source drug discovery: Highly potent antimalarial compounds derived from the tres cantos arylpyrroles

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

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