Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

被引：194

作者：

Kato, Nobutaka ^{[1
]}

Comer, Eamon ^{[1
]}

Sakata-Kato, Tomoyo ^{[2
]}

Sharma, Arvind ^{[3
]}

Sharma, Manmohan ^{[3
]}

Maetani, Micah ^{[1
,4
]}

Bastien, Jessica ^{[1
]}

Brancucci, Nicolas M. ^{[2
]}

Bittker, Joshua A. ^{[1
]}

Corey, Victoria ^{[5
]}

Clarke, David ^{[2
]}

Derbyshire, Emily R. ^{[1
,6
,7
,8
]}

Dornan, Gillian L. ^{[9
]}

Duffy, Sandra ^{[10
]}

Eckley, Sean ^{[11
]}

Itoe, Maurice A. ^{[2
]}

Koolen, Karin M. J. ^{[12
]}

Lewis, Timothy A. ^{[1
]}

Lui, Ping S. ^{[2
]}

Lukens, Amanda K. ^{[1
,2
]}

Lund, Emily ^{[2
]}

March, Sandra ^{[1
,13
]}

Meibalan, Elamaran ^{[2
]}

Meier, Bennett C. ^{[1
,4
]}

McPhail, Jacob A. ^{[9
]}

Mitasev, Branko ^{[11
]}

Moss, Eli L. ^{[1
]}

Sayes, Morgane ^{[1
]}

Van Gessel, Yvonne ^{[11
]}

Wawer, Mathias J. ^{[1
]}

Yoshinaga, Takashi ^{[14
]}

Zeeman, Anne-Marie ^{[15
]}

Avery, Vicky M. ^{[10
]}

Bhatia, Sangeeta N. ^{[1
,13
]}

Burke, John E. ^{[9
]}

Catteruccia, Flaminia ^{[2
]}

Clardy, Jon C. ^{[1
,6
]}

Clemons, Paul A. ^{[1
]}

Dechering, Koen J. ^{[12
]}

Duvall, Jeremy R. ^{[1
]}

Foley, Michael A. ^{[1
]}

Gusovsky, Fabian ^{[11
]}

Kocken, Clemens H. M. ^{[15
]}

Marti, Matthias ^{[2
]}

Morningstar, Marshall L. ^{[1
]}

Munoz, Benito ^{[1
]}

Neafsey, Daniel E. ^{[1
]}

Sharma, Amit ^{[3
]}

Winzeler, Elizabeth A. ^{[5
]}

Wirth, Dyann F. ^{[1
,2
]}

机构：

[1] Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA

[2] Harvard TH Chan Sch Publ Hlth, 665 Huntington Ave Boston, Boston, MA 02115 USA

[3] Int Ctr Genet Engn & Biotechnol, Mol Med Grp, Aruna Asaf Ali Rd, New Delhi 110067, India

[4] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA

[5] Univ Calif San Diego, Sch Med, 9500 Gilman Dr 0760, La Jolla, CA 92093 USA

[6] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, 240 Longwood Ave, Boston, MA 02115 USA

[7] Duke Univ, Dept Chem, 124 Sci Dr, Durham, NC 27708 USA

[8] Duke Univ, Dept Mol Genet & Microbiol, 124 Sci Dr, Durham, NC 27708 USA

[9] Univ Victoria, Dept Biochem & Microbiol, 270 Petch Hall, Victoria, BC V8P 5C2, Canada

[10] Griffith Univ, Eskitis Inst Drug Discovery, Nathan Campus, Brisbane, Qld 4111, Australia

[11] Eisai Inc, 4 Corp Dr, Andover, MA 01810 USA

[12] TropIQ Hlth Sci, Geert Grootepl 28,Huispost 268, NL-6525 GA Nijmegen, Netherlands

[13] MIT, Dept Elect Engn & Comp Sci, 500 Main St, Cambridge, MA 02142 USA

[14] Eisai & Co Ltd, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan

[15] Biochem Primate Res Ctr, Dept Parasitol, NL-2280 GH Rijswijk, Netherlands

来源：

NATURE | 2016年 / 538卷 / 7625期

基金：

英国惠康基金; 美国国家科学基金会;

关键词：

TRANSFER-RNA SYNTHETASE; PLASMODIUM-FALCIPARUM; DRUG DISCOVERY; HEPATIC STAGES; MALARIA; TARGETS; MODEL; ASSAY; LEAD; IDENTIFICATION;

D O I：

10.1038/nature19804

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：344 / +

页数：22

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