Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B-NS3 Protease

doi:10.1002/cmdc.201200497

	Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B-NS3 Protease
	Hammamy, M. Zouhir 3; Haase, Caroline 4,5; Hammami, Maya 3; Hilgenfeld, Rolf 1,2,4,5; Steinmetzer, Torsten 3
刊名	CHEMMEDCHEM
	2013-02
卷号	8 期号:2 页码:231-241
关键词	enzyme kinetics inhibitors NS2B-NS3 protease West Nile virus X-ray structure
ISSN号	1860-7179
DOI	10.1002/cmdc.201200497
文献子类	Article
英文摘要	A series of new substrate analogue inhibitors of the WNV NS2BNS3 protease containing decarboxylated arginine mimetics at the P1 position was developed. Among the various analogues, trans-(4-guanidino)cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue. In combination with dichloro-substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of <0.2 mu M were obtained. These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin-like serine proteases thrombin, factor Xa, and matriptase. A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3,4-dichlorophenylacetyl-Lys-Lys-GCMA (Ki=0.13 mu M). The inhibitor adopts a horseshoe-like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom. These inhibitors are stable, readily accessible, and have a noncovalent binding mode. Therefore, they may serve as suitable lead structures for further development.
资助项目	Yousef Jameel Scholarship Fund[00000000] ; European Commission[HEALTH-F3-2010-260644] ; Schleswig-Holstein Innovation Fund[00000000] ; Chinese Academy of Sciences[2010T1S6]
WOS关键词	X-RAY DATA ; NS3 PROTEASE ; THROMBIN INHIBITORS ; SERINE-PROTEASE ; HIGHLY POTENT ; SELECTIVE INHIBITORS ; ANTIVIRAL ACTIVITY ; NS2B/NS3 PROTEASE ; DENGUE VIRUS ; DATA QUALITY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-V C H VERLAG GMBH
WOS记录号	WOS:000314172700006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277749]
专题	中国科学院上海药物研究所
通讯作者	Hammamy, M. Zouhir
作者单位	1.DESY, Lab Struct Biol Infect & Inflammat, D-22603 Hamburg, Germany 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Univ Marburg, Inst Pharmaceut Chem, D-35032 Marburg, Germany; 4.Med Univ Lubeck, Ctr Struct & Cell Biol, Inst Biochem, D-23538 Lubeck, Germany; 5.Univ Lubeck, German Ctr Infect Res DZIF, Lubeck, Germany;
推荐引用方式 GB/T 7714	Hammamy, M. Zouhir,Haase, Caroline,Hammami, Maya,et al. Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B-NS3 Protease[J]. CHEMMEDCHEM,2013,8(2):231-241.
APA	Hammamy, M. Zouhir,Haase, Caroline,Hammami, Maya,Hilgenfeld, Rolf,&Steinmetzer, Torsten.(2013).Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B-NS3 Protease.CHEMMEDCHEM,8(2),231-241.
MLA	Hammamy, M. Zouhir,et al."Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B-NS3 Protease".CHEMMEDCHEM 8.2(2013):231-241.