Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.
Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.
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DOI：
10.1021/acs.jmedchem.2c00611
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发表时间：
2022-07-14
影响因子：
7.3
通讯作者：
Lin, Gang
中科院分区：
文献类型：
--
作者：
Zhang, Hao;Ginn, John;Zhan, Wenhu;Liu, Yi J.;Leung, Annie;Toita, Akinori;Okamoto, Rei;Wong, Tzu-Tshin;Imaeda, Toshihiro;Hara, Ryoma;Yukawa, Takafumi;Michino, Mayako;Vendome, Jeremie;Beuming, Thijs;Sato, Kenjiro;Aso, Kazuyoshi;Meinke, Peter T.;Nathan, Carl F.;Kirkman, Laura A.;Lin, Gang
疟疾每年有超过 2 亿病例和近 50 万人死亡，对全球健康构成威胁，特别是在发展中国家。恶性疟原虫是导致最严重疾病的寄生虫，它已经对所有抗疟药物产生了耐药性。对一线抗疟药物青蒿素和青蒿素联合疗法的耐药性在东南亚普遍存在，并且在撒哈拉以南非洲地区正在出现。恶性疟原虫蛋白酶体是一个有吸引力的抗疟靶标，因为它的抑制作用可以在寄生虫生命周期的多个阶段杀死寄生虫，并恢复因 Kelch K13 突变而产生耐药性的寄生虫对青蒿素的敏感性。在这里，我们详细介绍了我们在结构分析和药代动力学特性的指导下开发非共价大环肽疟疾蛋白酶体抑制剂的努力，从而产生了一种有效的、物种选择性的、代谢稳定的抑制剂。
With over 200 million cases and close to half million deaths each year, malaria is a threat to global health, particularly in developing countries. Plasmodium falciparum, the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa. The P. falciparum proteasome is an attractive antimalarial target because its inhibition kills the parasite at multiple stages of its life cycle and restores artemisinin sensitivity in parasites that have become resistant through mutation in Kelch K13. Here we detail our efforts to develop noncovalent, macrocyclic peptide malaria proteasome inhibitors, guided by structural analysis and pharmacokinetic properties, leading to a potent, species-selective, metabolically stable inhibitor.
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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：
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
影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
影响因子：
5.4
作者：
Li, Hao;Bogyo, Matthew;da Fonseca, Paula C. A.
通讯作者：
da Fonseca, Paula C. A.
影响因子：
6.7
作者：
Stokes, Barbara H.;Yoo, Euna;Fidock, David A.
通讯作者：
Fidock, David A.