Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance Journal Article
| 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.; Kirkman, L. A.; Lin, G. |
| Article Title: | Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance |
| 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. © 2023 Elsevier Ltd |
| Keywords: | ubiquitin; animal; metabolism; animals; proteasome; proteasome inhibitor; proteasome endopeptidase complex; drug resistance; chemistry; pharmacophore; antimalarial agent; antimalarials; malaria; hybrid; plasmodium; parasite; parasites; artemisinin; artemisinin resistance; dual-resistance; in vivo efficacy; mouse models of malaria infection; recrudescence; artemisinin derivative; artemisinins |
| Journal Title: | Cell Chemical Biology |
| Volume: | 30 |
| Issue: | 5 |
| ISSN: | 2451-9456 |
| Publisher: | Cell Press |
| Date Published: | 2023-05-18 |
| Start Page: | 457 |
| End Page: | 469.e11 |
| Language: | English |
| DOI: | 10.1016/j.chembiol.2023.04.006 |
| PUBMED: | 37148884 |
| PROVIDER: | scopus |
| PMCID: | PMC10240386 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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