Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome

Deni, I. et al. (2023) Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome. Cell Chemical Biology, 30(5), 470-485.e6. (doi: 10.1016/j.chembiol.2023.03.002) (PMID:36963402) (PMCID:PMC10198959)

Abstract

The Plasmodium falciparum proteasome constitutes a promising antimalarial target, with multiple chemotypes potently and selectively inhibiting parasite proliferation and synergizing with the first-line artemisinin drugs, including against artemisinin-resistant parasites. We compared resistance profiles of vinyl sulfone, epoxyketone, macrocyclic peptide, and asparagine ethylenediamine inhibitors and report that the vinyl sulfones were potent even against mutant parasites resistant to other proteasome inhibitors and did not readily select for resistance, particularly WLL that displays covalent and irreversible binding to the catalytic β2 and β5 proteasome subunits. We also observed instances of collateral hypersensitivity, whereby resistance to one inhibitor could sensitize parasites to distinct chemotypes. Proteasome selectivity was confirmed using CRISPR/Cas9-edited mutant and conditional knockdown parasites. Molecular modeling of proteasome mutations suggested spatial contraction of the β5 P1 binding pocket, compromising compound binding. Dual targeting of P. falciparum proteasome subunits using covalent inhibitors provides a potential strategy for restoring artemisinin activity and combating the spread of drug-resistant malaria.

• Item Type: Articles
• Additional Information: This work was supported in part by the NIH (R21/R33 AI125781 to M.B., D.A.F.; R01 AI109023 to D.A.F.; R01 AI143714 to G.L.; R21 AI146387, R21 AI133393, and R01 AI158612 to A.J.O.). Additional funding was provided by the Department of Defense (W81XWH2210520 to D.A.F., M.B., L.A.K., G.L., A.J.O., W.H.G., and W81XWH2210015 to C.L.N.). Financial support was also provided by the Bill & Melinda Gates Foundation (INV-037899 to J.A., A.J.O., W.H.G.; OPP1162467 to J.C.N.). C.L.N. gratefully acknowledges start-up funds and a Diversity Fund grant from the University of Nebraska Medical Center. P.C.A.d.F. and S.A. acknowledge support from the University of Glasgow.
• Keywords: Artemisinin, conditional knockdown, malaria, minimum inoculum of resistance, proteasome, drug discovery, covalent inhibitors, CRISPR/Cas9 gene editing, molecular modeling, Plasmodium falciparum.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stokes, Ms Barbara and da Fonseca, Professor Paula and Akbar, Dr Shirin
• Authors: Deni, I., Stokes, B. H., Ward, K. E., Fairhurst, K. J., Pasaje, C. F. A., Yeo, T., Akbar, S., Park, H., Muir, R., Bick, D. S., Zhan, W., Zhang, H., Liu, Y. J., Ng, C. L., Kirkman, L. A., Almaliti, J., Gould, A. E., Duffey, M., O'Donoghue, A. J., Uhlemann, A.-C., Niles, J. C., da Fonseca, P. C. A., Gerwick, W. H., Lin, G., Bogyo, M., and Fidock, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Cell Chemical Biology
• Publisher: Elsevier (Cell Press)
• ISSN: 2451-9456
• ISSN (Online): 2451-9448
• Published Online: 23 March 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Cell Chemical Biology 30(5): 470-485.e6
• Publisher Policy: Reproduced under a Creative Commons License