Journal article
The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria
M De Lera Ruiz, P Favuzza, Z Guo, L Zhao, B Hu, Z Lei, D Zhan, N Murgolo, CW Boyce, M Vavrek, J Thompson, A Ngo, KE Jarman, J Robbins, J Boddey, BE Sleebs, KN Lowes, AF Cowman, DB Olsen, JA McCauley
ACS Medicinal Chemistry Letters | Published : 2022
Abstract
Drug resistance to first-line antimalarials─including artemisinin─is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimiza..
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Awarded by Wellcome Trust
Funding Acknowledgements
This work was made possible through support of The Wellcome Trust [109662/Z/15/Z, 2027/Z/16/Z] . We thank Tanweer Khan, Andrew Stamford, Brian McKittrick, and Jared Cumming for their ideas and support of the initial screening campaign. We thank Michael J. Kelly III, PhilippeG. Nantermet, and Jacqueline B. Fine for project and manuscript preparation support. We also thank Benjamin D. Sherry for the scale-up of WM382.