Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance (original) (raw)
Zhan, W. et al. (2023) Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.Cell Chemical Biology, 30(5), 457-469.e11. (doi: 10.1016/j.chembiol.2023.04.006) (PMID:37148884) (PMCID:PMC10240386)
Abstract
Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite’s own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation. When damaged proteins enter the proteasome, their attached PIs inhibit protease function, potentiating the parasiticidal action of ART and overcoming ART resistance. Binding of the PI moiety to the proteasome active site is enhanced by distal interactions of the extended attached peptides, providing a mechanism to overcome PI resistance. ATZs have an extra mode of action beyond that of each component, thereby overcoming resistance to both components, while avoiding transient monotherapy seen when individual agents have disparate pharmacokinetic profiles.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work is supported by R21AI153485 (G.L.), in part by R01AI143714 (G.L.), in part by U19AI089672 (L.C.), in part by a Brockman Medical Foundation Medical Research Grant (L.K.), and by the Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine (C.N.). This work was supported by grants from the Wellcome Trust to A.P.W (083811/Z/07/Z, 107046/Z/15/Z, and 104111/Z/14/Z). N.V.S is a Commonwealth Doctoral Scholar (MWCS-2017-789), funded by the UK Government. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. |
| Keywords: | Plasmodium, malaria, antimalarial, proteasome, falciparum, berghei. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Simwela, Nelson and Waters, Professor Andy |
| Authors: | Zhan, W., Li, D., Subramanyaswamy, S. B., Liu, Y. J., Yang, C., Zhang, H., Harris, J. C., Wang, R., Zhu, S., Rocha, H., Sherman, J., Qin, J., Herring, M., Simwela, N. V., Waters, A. P., Sukenick, G., Cui, L., Rodriguez, A., Deng, H., Nathan, C. F., and Lin, G. |
| Subjects: | Q Science > QR MicrobiologyR Medicine > RM Therapeutics. Pharmacology |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Research Group: | Waters |
| Journal Name: | Cell Chemical Biology |
| Publisher: | Elsevier (Cell Press) |
| ISSN: | 2451-9456 |
| ISSN (Online): | 2451-9448 |
| Published Online: | 05 May 2023 |
| Copyright Holders: | Copyright © 2023 Elsevier Ltd. |
| First Published: | First published in Cell Chemical Biology 30(5):457-469.e11 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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Funder and Project Information
Conditional translational repression: a core regulatory mechanism of gene expression during development of the malaria parasite.
Andrew Waters
083811/Z/07/Z
SII - Parasitology
Gene expression in Plasmodium parasites: the molecular mechanics of gametocytogenesis (and variant transcription of genes)
Andrew Waters
107046/Z/15/Z
SII - Parasitology
The Wellcome Centre for Molecular Parasitology ( Core Support )
Andrew Waters
104111/Z/14/Z
SII - Parasitology
Deposit and Record Details
| ID Code: | 350129 |
|---|---|
| Depositing User: | Professor Andy Waters |
| Datestamp: | 14 Mar 2025 10:10 |
| Last Modified: | 02 Apr 2025 09:10 |
| Date of acceptance: | 6 April 2023 |
| Date of first online publication: | 5 May 2023 |
| Date Deposited: | 12 March 2025 |
| Data Availability Statement: | No |