Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity.
Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity.
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DOI：
10.1021/acs.jmedchem.7b00671
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发表时间：
2017-08-10
影响因子：
7.3
通讯作者：
Ottilie S
中科院分区：
文献类型：
--
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
天然衍生的化合物是我们大部分药典的基础，特别是在抗增殖和抗感染药物类别中。在这里，我们报告说，一种天然衍生的分子称为carmaphycin B是一种有效的抑制剂，对无性和有性血液阶段的疟疾感染。在充分表征的药物敏感性酵母模型中使用计算机分子对接和体外定向进化的组合，我们确定这些化合物靶向蛋白酶体的β5亚基。这些研究使用从恶性疟原虫分离的蛋白酶体的体外抑制试验进行了验证。由于卡马霉素B对哺乳动物细胞有毒，我们合成了一系列化学类似物，这些化学类似物降低宿主细胞毒性，同时保持血液阶段和杀配子抗疟活性和蛋白酶体抑制。这项研究描述了一类有前途的新的抗疟化合物的基础上carmaphycin B支架，以及几个化学结构特征，有助于提高抗疟特异性。
Naturally derived chemical compounds are the foundation of much of our pharmacopeia, especially in antiproliferative and anti-infective drug classes. Here, we report that a naturally derived molecule called carmaphycin B is a potent inhibitor against both the asexual and sexual blood stages of malaria infection. Using a combination of in silico molecular docking and in vitro directed evolution in a well-characterized drug-sensitive yeast model, we determined that these compounds target the β5 subunit of the proteasome. These studies were validated using in vitro inhibition assays with proteasomes isolated from Plasmodium falciparum. As carmaphycin B is toxic to mammalian cells, we synthesized a series of chemical analogs that reduce host cell toxicity while maintaining blood-stage and gametocytocidal antimalarial activity and proteasome inhibition. This study describes a promising new class of antimalarial compound based on the carmaphycin B scaffold, as well as several chemical structural features that serve to enhance antimalarial specificity.
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影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
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：
5.7
作者：
Harshbarger, Wayne;Miller, Chase;Sacchettini, James
通讯作者：
Sacchettini, James
影响因子：
4.6
作者：
Goldgof GM;Durrant JD;Ottilie S;Vigil E;Allen KE;Gunawan F;Kostylev M;Henderson KA;Yang J;Schenken J;LaMonte GM;Manary MJ;Murao A;Nachon M;Murray R;Prescott M;McNamara CW;Slayman CW;Amaro RE;Suzuki Y;Winzeler EA
通讯作者：
Winzeler EA
影响因子：
3.3
作者：
Finley, Daniel;Ulrich, Helle D.;Kaiser, Peter
通讯作者：
Kaiser, Peter