Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.
Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome.
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DOI：
10.1073/pnas.2107213118
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发表时间：
2021-09-28
影响因子：
11.1
通讯作者：
Tilley L
中科院分区：
文献类型：
--
作者：
Xie SC;Metcalfe RD;Mizutani H;Puhalovich T;Hanssen E;Morton CJ;Du Y;Dogovski C;Huang SC;Ciavarri J;Hales P;Griffin RJ;Cohen LH;Chuang BC;Wittlin S;Deni I;Yeo T;Ward KE;Barry DC;Liu B;Gillett DL;Crespo-Fernandez BF;Ottilie S;Mittal N;Churchyard A;Ferguson D;Aguiar ACC;Guido RVC;Baum J;Hanson KK;Winzeler EA;Gamo FJ;Fidock DA;Baud D;Parker MW;Brand S;Dick LR;Griffin MDW;Gould AE;Tilley L
Here, we describe inhibitors of the Plasmodium proteasome, an enzymatic complex that malaria parasites rely on to degrade proteins. Starting from inhibitors developed to treat cancer, derivatives were designed and synthesized with the aim of increasing potency against the Plasmodium proteasome and decreasing activity against the human enzyme. Biochemical and cellular assays identified compounds that exhibit selectivity and potency, both in vitro and in vivo, at different stages of the parasite’s lifecycle. Cryo-electron microscopy revealed that the inhibitors bind in a hydrophobic pocket that is structurally different in the human proteasome—underpinning their selectivity. The work will help develop antimalarial therapeutics, which are desperately needed to treat a disease that kills nearly half a million people annually. The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax. They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.
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影响因子：
11.8
作者：
Bergmann C;van Loon W;Habarugira F;Tacoli C;Jäger JC;Savelsberg D;Nshimiyimana F;Rwamugema E;Mbarushimana D;Ndoli J;Sendegeya A;Bayingana C;Mockenhaupt FP
通讯作者：
Mockenhaupt FP
影响因子：
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Bogyo M
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通讯作者：
Angulo-Barturen, Inigo
影响因子：
6.7
作者：
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通讯作者：
Fidock, David A.