Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.
Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.
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DOI：
10.1002/anie.202015845
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发表时间：
2021-04-19
期刊：
影响因子：
--
通讯作者：
Lin G
中科院分区：
文献类型：
--
作者：
Zhan W;Zhang H;Ginn J;Leung A;Liu YJ;Michino M;Toita A;Okamoto R;Wong TT;Imaeda T;Hara R;Yukawa T;Chelebieva S;Tumwebaze PK;Lafuente-Monasterio MJ;Martinez-Martinez MS;Vendome J;Beuming T;Sato K;Aso K;Rosenthal PJ;Cooper RA;Meinke PT;Nathan CF;Kirkman LA;Lin G
恶性疟原虫蛋白酶体（Pf20S）抑制剂在多个阶段（红细胞期、配子体期、肝期和配子活化）对疟原虫具有活性，表明选择性Pf20S抑制剂具有成为治疗性、预防性和阻断传播的抗疟药的潜力。从报道的化合物开始，我们开发了一种非共价的大环肽疟疾蛋白酶体抑制剂，具有高物种选择性和改善的药代动力学特性。该化合物表现出对恶性疟原虫蛋白酶体的β5亚基的特异性、时间依赖性抑制，在体外杀死青蒿素敏感和青蒿素抗性恶性疟原虫分离株，并减少人源化恶性疟原虫感染小鼠中的寄生虫血症。Pf20S抑制剂具有成为治疗性、预防性和阻断传播的抗疟药的潜力。我们提出了一种新的和高度物种选择性的疟疾蛋白酶体抑制剂，有效地减少感染恶性疟原虫，最致命的疟原虫寄生虫的人源化小鼠的寄生虫血症。
Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages – erythrocytic stages, gametocyte stages, liver stages and gamete activation, indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Plasmodium falciparum proteasome, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice. Pf20S inhibitors possess the potential to be therapeutic, prophylactic and transmission-blocking antimalarials. We present a novel and highly species-selective malaria proteasome inhibitor that potently reduced parasitemia in humanized mice infected with P. falciparum, the most deadly plasmodium parasites.
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