Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin s with an unprecedented binding mode

被引:25
作者
Inagaki, Hiroaki
Tsuruoka, Hiroyuki
Hornsby, Michael
Lesley, Scott A.
Spraggon, Glen
Ellman, Jonathan A.
机构
[1] Novartis Res Fdn, Genome Inst, San Diego, CA 92121 USA
[2] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA
关键词
D O I
10.1021/jm070111+
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The substrate activity screening (SAS) method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain a novel (2-arylphenoxy)acetaldehyde inhibitor, 2, with a 0.49 mu M K-i value (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). In this paper we disclose the X-ray structure of a complex between cathepsin S and inhibitor 2 which reveals an unprecedented binding mode. On the basis of this structure, additional 2-biaryloxy substrates with greatly increased cleavage efficiency were designed. Conversion of the optimized substrates to the corresponding aldehyde inhibitors yielded a low molecular weight (304 Daltons) and potent (9.6 nM) cathepsin S inhibitor that showed from 100- to > 1000-fold selectivity relative to cathepsins B, L, and K.
引用
收藏
页码:2693 / 2699
页数:7
相关论文
共 18 条
[1]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[2]   L-TRANS-EPOXYSUCCINYL-LEUCYLAMIDO(4-GUANIDINO)BUTANE (E-64) AND ITS ANALOGS AS INHIBITORS OF CYSTEINE PROTEINASES INCLUDING CATHEPSINS B, H AND L [J].
BARRETT, AJ ;
KEMBHAVI, AA ;
BROWN, MA ;
KIRSCHKE, H ;
KNIGHT, CG ;
TAMAI, M ;
HANADA, K .
BIOCHEMICAL JOURNAL, 1982, 201 (01) :189-198
[3]   TIGHT-BINDING INHIBITORS .2. NON-STEADY STATE NATURE OF INHIBITION OF MILK XANTHINE-OXIDASE BY ALLOPURINOL AND ALLOXANTHINE AND OF HUMAN ERYTHROCYTIC ADENOSINE DEAMINASE BY COFORMYCIN [J].
CHA, S ;
AGARWAL, RP ;
PARKS, RE .
BIOCHEMICAL PHARMACOLOGY, 1975, 24 (23) :2187-2197
[4]   Antiferroelectric switchable mesophases of nonchiral bent-core liquid crystals containing fluorinated central cores [J].
Dantlgraber, G ;
Shen, D ;
Diele, S ;
Tschierske, C .
CHEMISTRY OF MATERIALS, 2002, 14 (03) :1149-1158
[5]   Coot:: model-building tools for molecular graphics [J].
Emsley, P ;
Cowtan, K .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132
[6]   Cathepsin S inhibitors [J].
Leroy, V ;
Thurairatnam, S .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2004, 14 (03) :301-311
[7]   Design and synthesis of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part I [J].
Liu, H ;
Tully, DC ;
Epple, R ;
Bursulaya, B ;
Li, J ;
Harris, JL ;
Williams, JA ;
Russo, R ;
Tumanut, C ;
Roberts, MJ ;
Alper, PB ;
He, Y ;
Karanewsky, DS .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (22) :4979-4984
[8]   Expedient solid-phase synthesis of fluorogenic protease substrates using the 7-amino-4-carbamoylmethylcoumarin (ACC) fluorophore [J].
Maly, DJ ;
Leonetti, F ;
Backes, BJ ;
Dauber, DS ;
Harris, JL ;
Craik, CS ;
Ellman, JA .
JOURNAL OF ORGANIC CHEMISTRY, 2002, 67 (03) :910-915
[9]   Refinement of macromolecular structures by the maximum-likelihood method [J].
Murshudov, GN ;
Vagin, AA ;
Dodson, EJ .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1997, 53 :240-255
[10]   Keto-1,3,4-oxadiazoles as cathepsin K inhibitors [J].
Palmer, JT ;
Hirschbein, BL ;
Cheung, H ;
McCarter, J ;
Janc, JW ;
Yu, ZW ;
Wesolowski, G .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (11) :2909-2914