Design and Synthesis of Potent, Selective Inhibitors of Matriptase

被引：58

作者：

Colombo, Eloic ^{[1
]}

Desilets, Antoine ^{[1
]}

Duchene, Dominic ^{[2
]}

Chagnon, Felix ^{[1
]}

Najmanovich, Rafael ^{[2
]}

Leduc, Richard ^{[1
]}

Marsault, Eric ^{[1
]}

机构：

[1] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Pharmacol, Sherbrooke, PQ J1H 5N4, Canada

[2] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Biochem, Sherbrooke, PQ J1H 5N4, Canada

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 07期

基金：

加拿大健康研究院;

关键词：

matriptase; type II transmembrane serine protease; slow tight-binding inhibitor; TRANSMEMBRANE SERINE-PROTEASE; AUTOSOMAL RECESSIVE ICHTHYOSIS; IDENTIFICATION; ACTIVATOR; MUTATION;

D O I：

10.1021/ml3000534

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight binding inhibitors of matriptase, which mimic the P1-P4 substrate recognition sequence of the enzyme. Preliminary structure-activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine. proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.

引用

页码：530 / 534

页数：5

共 33 条

[1] Membrane-Anchored Serine Proteases in Health and Disease [J].

Antalis, Toni M. ;

Bugge, Thomas H. ;

Wu, Qingyu .

PROTEASES IN HEALTH AND DISEASE, 2011, 99 :1-50

[2] Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase [J].

Basel-Vanagaite, Lina ;

Attia, Revital ;

Ishida-Yamamoto, Akemi ;

Rainshtein, Limor ;

Ben Amitai, Dan ;

Lurie, Raziel ;

Pasmanik-Chor, Metsada ;

Indelman, Margarita ;

Zvulunov, Alex ;

Saban, Shirley ;

Magal, Nurit ;

Sprecher, Eli ;

Shohat, Mordechai .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 80 (03) :467-477

[3] Probing the substrate specificities of matriptase, matriptase-2, hepsin and DESC1 with internally quenched fluorescent peptides [J].

Beliveau, Francois ;

Desilets, Antoine ;

Leduc, Richard .

FEBS JOURNAL, 2009, 276 (08) :2213-2226

[4] The Protein Data Bank [J].

Berman, HM ;

Westbrook, J ;

Feng, Z ;

Gilliland, G ;

Bhat, TN ;

Weissig, H ;

Shindyalov, IN ;

Bourne, PE .

NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242

[5]

BIETH JG, 1995, METHOD ENZYMOL, V248, P59

[6]

Copeland R., 2000, PRACTICAL INTRO STRU, P1

[7] In-depth study of tripeptide-based α-ketoheterocycles as inhibitors of thrombin.: Effective utilization of the S1′ subsite and its implications to structure-based drug design [J].

Costanzo, MJ ;

Almond, HR ;

Hecker, LR ;

Schott, MR ;

Yabut, SC ;

Zhang, HC ;

Andrade-Gordon, P ;

Corcoran, TW ;

Giardino, EC ;

Kauffman, JA ;

Lewis, JM ;

de Garavilla, L ;

Haertlein, BJ ;

Maryanoff, BE .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (06) :1984-2008

[8] Inhibition of human matriptase by eglin c variants [J].

Désilets, A ;

Longpré, JM ;

Beaulieu, ME ;

Leduc, R .

FEBS LETTERS, 2006, 580 (09) :2227-2232

[9] Mutation G827R in matriptase causing autosomal recessive ichthyosis with hypotrichosis yields an inactive protease [J].

Desilets, Antoine ;

Beliveau, Francois ;

Vandal, Guillaume ;

McDuff, Francois-Olivier ;

Lavigne, Pierre ;

Leduc, Richard .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (16) :10535-10542

[10] Structure-based approach for the discovery of bis-benzamidines as novel inhibitors of matriptase [J].

Enyedy, IJ ;

Lee, SL ;

Kuo, AH ;

Dickson, RB ;

Lin, CY ;

Wang, SM .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (09) :1349-1355

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