Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome.
Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome.
复制标题
DOI：
10.1016/j.chembiol.2023.03.002
复制
发表时间：
2023-05-18
影响因子：
8.6
通讯作者：
Fidock, David A.
中科院分区：
文献类型：
--
作者：
Deni, Ioanna;Stokes, Barbara H.;Ward, Kurt E.;Fairhurst, Kate J.;Pasaje, Charisse Flerida A.;Yeo, Tomas;Akbar, Shirin;Park, Heekuk;Muir, Ryan;Bick, Daniella S.;Zhan, Wenhu;Zhang, Hao;Liu, Yi Jing;Ng, Caroline L.;Kirkman, Laura A.;Almaliti, Jehad;Gould, Alexandra E.;Duffey, Maelle;O'Donoghue, Anthony J.;Uhlemann, Anne-Catrin;Niles, Jacquin C.;da Fonseca, Paula C. A.;Gerwick, William H.;Lin, Gang;Bogyo, Matthew;Fidock, David A.
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. Multiple proteasome-specific chemotypes can potently inhibit P. falciparum growth Resistance can arise via mutations in the β2, β5 or β6 subunits of the 20S proteasome core particle, or in the 19S regulatory particle WLL has a minimal resistance risk, attributable to its covalent binding to both β2 and β5 Resistance to some chemotypes can produce collateral sensitivity to other compounds Inhibitors of the Plasmodium falciparum proteasome have emerged as leading antimalarial candidates. Herein, Deni and Stokes et al. profile a range of diverse chemotypes and identify the vinyl sulfone WLL as the least susceptible to resistance, likely attributable to its covalent, irreversible binding to the β2 and β5 catalytic subunits.
登录
查看更多内容
影响因子：
16.6
作者：
Dekel E;Yaffe D;Rosenhek-Goldian I;Ben-Nissan G;Ofir-Birin Y;Morandi MI;Ziv T;Sisquella X;Pimentel MA;Nebl T;Kapp E;Ohana Daniel Y;Karam PA;Alfandari D;Rotkopf R;Malihi S;Temin TB;Mullick D;Revach OY;Rudik A;Gov NS;Azuri I;Porat Z;Bergamaschi G;Sorkin R;Wuite GJL;Avinoam O;Carvalho TG;Cohen SR;Sharon M;Regev-Rudzki N
通讯作者：
Regev-Rudzki N
影响因子：
15
作者：
Li, Hao;Tsu, Christopher;Blackburn, Christopher;Li, Gang;Hales, Paul;Dick, Lawrence;Bogyo, Matthew
通讯作者：
Bogyo, Matthew
影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
DOI：
10.1016/s1473-3099(21)00252-8
发表时间：
2021-12
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
McCarthy JS;Yalkinoglu Ö;Odedra A;Webster R;Oeuvray C;Tappert A;Bezuidenhout D;Giddins MJ;Dhingra SK;Fidock DA;Marquart L;Webb L;Yin X;Khandelwal A;Bagchus WM
通讯作者：
Bagchus WM
影响因子：
7.3
作者：
LaMonte GM;Almaliti J;Bibo-Verdugo B;Keller L;Zou BY;Yang J;Antonova-Koch Y;Orjuela-Sanchez P;Boyle CA;Vigil E;Wang L;Goldgof GM;Gerwick L;O'Donoghue AJ;Winzeler EA;Gerwick WH;Ottilie S
通讯作者：
Ottilie S