Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

被引：57

作者：

Crowther, Gregory J. ^{[2
]}

Napuli, Alberto J. ^{[2
]}

Gilligan, James H. ^{[1
]}

Gagaring, Kerstin ^{[1
]}

Borboa, Rachel ^{[1
]}

Francek, Carolyn ^{[1
]}

Chen, Zhong ^{[1
]}

Dagostino, Eleanor F. ^{[1
]}

Stockmyer, Justin B. ^{[1
]}

Wang, Yu ^{[1
]}

Rodenbough, Philip P. ^{[2
]}

Castaneda, Lisa J. ^{[2
]}

Leibly, David J. ^{[2
]}

Bhandari, Janhavi ^{[2
]}

Gelb, Michael H. ^{[2
]}

Brinker, Achim ^{[1
]}

Engels, Ingo H. ^{[1
]}

Taylor, Jennifer ^{[1
]}

Chatterjee, Arnab K. ^{[1
]}

Fantauzzi, Pascal ^{[3
]}

Glynne, Richard J. ^{[1
]}

Van Voorhis, Wesley C. ^{[2
]}

Kuhen, Kelli L. ^{[1
]}

机构：

[1] Novartis Res Fdn GNF, Genom Inst, San Diego, CA 92121 USA

[2] Univ Washington, Seattle, WA 98195 USA

[3] Med Malaria Venture, Geneva, Switzerland

来源：

MOLECULAR AND BIOCHEMICAL PARASITOLOGY | 2011年 / 175卷 / 01期

关键词：

Target-based drug development; Enzyme activity assays; Antimalarial compounds; PLASMODIUM-FALCIPARUM MALARIA; L-HOMOCYSTEINE HYDROLASE; GLUTAMATE-DEHYDROGENASE; ADENYLOSUCCINATE SYNTHETASE; MOLECULAR CHARACTERIZATION; APICOMPLEXAN PARASITES; TRYPANOSOMA-BRUCEI; QUININE RESISTANCE; CRYSTAL-STRUCTURE; CHOLINE KINASE;

D O I：

10.1016/j.molbiopara.2010.08.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC50 values below 1.25 mu M. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, drug-gability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology. (C) 2010 Elsevier B.V. All rights reserved.

引用

页码：21 / 29

页数：9