Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
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DOI：
10.1038/nature19804
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发表时间：
2016-10-20
期刊：
影响因子：
64.8
通讯作者：
Schreiber SL
中科院分区：
文献类型：
--
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
迄今为止，抗疟疾药物主要有两种来源：天然产物和合成类药物化合物。在这里，我们调查是否可以发现具有新的作用机制的抗疟药，使用具有三维特征的合成化合物，让人联想到天然产物，并在典型的筛选集合中代表性不足的多样化集合。我们报告了这些化合物的鉴定，这些化合物具有先前报道和未描述的作用机制，包括一系列双环氮杂环丁烷，其抑制新的抗疟靶点，苯丙氨酰-tRNA合成酶。这些分子在单次低剂量下对小鼠具有治疗作用，并在多个体内功效模型中显示出针对所有寄生虫生命阶段的活性。我们的研究结果确定了双环氮杂环丁烷类化合物，其具有治愈和预防疾病传播的潜力，并通过单次口服剂量保护高危人群，突出了多样性导向合成在揭示有希望的治疗靶点方面的优势。
Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
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DOI：
10.1038/nrmicro3138
发表时间：
2013-12
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.2
作者：
Heidebrecht, Richard W., Jr.;Mulrooney, Carol;Austin, Christopher P.;Barker, Robert H., Jr.;Beaudoin, Jennifer A.;Cheng, Ken Chih-Chien;Comer, Eamon;Dandapani, Sivaraman;Dick, Justin;Duvall, Jeremy R.;Ekland, Eric H.;Fidock, David A.;Fitzgerald, Mark E.;Foley, Michael;Guha, Rajarshi;Hinkson, Paul;Kramer, Martin;Lukens, Amanda K.;Masi, Daniela;Marcaurelle, Lisa A.;Su, Xin-Zhuan;Thomas, Craig J.;Weiwer, Michel;Wiegand, Roger C.;Wirth, Dyann;Xia, Menghang;Yuan, Jing;Zhao, Jinghua;Palmer, Michelle;Munoz, Benito;Schreiber, Stuart
通讯作者：
Schreiber, Stuart
影响因子：
4.4
作者：
Bhatt TK;Kapil C;Khan S;Jairajpuri MA;Sharma V;Santoni D;Silvestrini F;Pizzi E;Sharma A
通讯作者：
Sharma A
影响因子：
--
作者：
Burke, John E;Williams, Roger L
通讯作者：
Williams, Roger L
影响因子：
3
作者：
Ding XC;Ubben D;Wells TN
通讯作者：
Wells TN