Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.
Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.
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结构揭示恶性疟原虫对蛋白酶体抑制剂的抗性和侧系敏感性机制。
DOI：
10.1038/s41467-023-44077-2
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发表时间：
2023-12-14
影响因子：
16.6
通讯作者：
Lin, Gang
中科院分区：
文献类型：
--
作者：
Hsu, Hao-Chi;Li, Daqiang;Zhan, Wenhu;Ye, Jianxiang;Liu, Yi Jing;Leung, Annie;Qin, Junling;Crespo, Benigno;Gamo, Francisco-Javier;Zhang, Hao;Cui, Liwang;Roth, Alison;Kirkman, Laura A.;Li, Huilin;Lin, Gang
恶性疟原虫(Pf20S)的蛋白酶体是一个有利的药物靶点，因为它的抑制作用可以在恶性疟原虫生命周期的多个阶段杀死它，并与青蒿素协同作用。我们最近开发了一种大环肽TDI-8304，它对人蛋白酶体上的Pf20S具有高度的选择性，并在体外和体内对恶性疟原虫具有很强的抗药性。Pf20Sβ6亚基A117D突变使其对TDI8304产生抗性，但增强了三肽乙烯基砜β2抑制剂WLW-vS的酶抑制和抗寄生虫活性。在这里，我们介绍了Pf20S与Tdi-8304的高分辨冷冻EM结构，人的结构性蛋白酶体与Tdi-8304的高分辨冷冻EM结构，以及Pf20Sβ6A117D与WLW-VS的高分辨冷冻EM结构，从而深入了解Tdi-8304的物种选择性、对Tdi-8304的抗性以及与抗性相关的附带敏感性，包括Tdi-8304与野生型Pf20S中的β2和β5结合以及WLW-VS与Pf20Sβ6A117D中的β2和β5结合。我们进一步表明，TDI-8304对恶性疟原虫的杀灭速度与氯喹和青蒿素一样快，并在肝脏阶段对食蟹猴疟原虫有活性。这增加了人们对使用这些结构来促进Pf20S抑制剂的开发的兴趣，这些抑制剂针对多个蛋白酶体亚单位并限制耐药的出现。恶性疟原虫蛋白酶体(Pf20S)是一种很有前景的多阶段药物靶点。使用低温EM Hsu等人。报道寄生虫和人类蛋白酶体与最近开发的抑制剂TDI-8304复合的结构，以了解其物种选择性。
The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6A117D with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6A117D. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance. The proteasome of Plasmodium falciparum (Pf20S) is a promising multi-stage drug target. Using CryoEM Hsu et al. report the structures of parasite and human proteasome in complex with the recently developed inhibitor TDI-8304 to gain insights into its species selectivity.
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影响因子：
30.3
作者：
Gural N;Mancio-Silva L;Miller AB;Galstian A;Butty VL;Levine SS;Patrapuvich R;Desai SP;Mikolajczak SA;Kappe SHI;Fleming HE;March S;Sattabongkot J;Bhatia SN
通讯作者：
Bhatia SN
柬埔寨恶性疟原虫疟疾中的双氢青蒿素-哌喹抗药性：一项多地点前瞻性队列研究。
DOI：
10.1016/s1473-3099(15)00487-9
发表时间：
2016-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Amaratunga C;Lim P;Suon S;Sreng S;Mao S;Sopha C;Sam B;Dek D;Try V;Amato R;Blessborn D;Song L;Tullo GS;Fay MP;Anderson JM;Tarning J;Fairhurst RM
通讯作者：
Fairhurst RM
影响因子：
3
作者：
Linares, Maria;Viera, Sara;Gamo, Francisco-Javier
通讯作者：
Gamo, Francisco-Javier
影响因子：
6.7
作者：
Gnadig, Nina F.;Stokes, Barbara H.;Fidock, David A.
通讯作者：
Fidock, David A.
影响因子：
48
作者：
Punjani, Ali;Rubinstein, John L.;Brubaker, Marcus A.
通讯作者：
Brubaker, Marcus A.