Discovery of novel nuclear receotor modulating ligands: an for peptide interaction integral role profiling

被引:28
作者
Pearce, KH [1 ]
Iannone, MA [1 ]
Simmons, CA [1 ]
Gray, JG [1 ]
机构
[1] GlaxoSmithKline, Dept Gene Express & Prot Biochem, Discovery Res, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1016/S1359-6446(04)03201-5
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
There is currently a marketed drug for nearly every nuclear receptor for which the natural ligand has been identified. However, because of the complexity of signal transduction by this class of ligand-regulated transcription factors, few of these drugs have been optimized for pharmaceutical effectiveness. Over the past several years, structural and biochemical work has shed light on some of the ligand-induced features of nuclear receptors that enable them to trigger signal transduction cascades. This review will highlight the use of peptide interactions to cluster different classes of ligands and to identify novel nuclear receptor-modulating ligands as potential drug candidates. Phage display and a multiplexed peptide interaction assay are two of the technologies that are key to this approach. When used as part of a drug discovery platform, this type of biochemical characterization can bridge the gap between high-throughput chemical synthesis and disease model testing. Furthermore, the development of these methodologies is timely because there is a significant medical need for new and improved nuclear receptor drugs that retain beneficial effects but do not have undesired side effect activities.
引用
收藏
页码:741 / 751
页数:11
相关论文
共 69 条
[1]  
Auwerx J, 1999, CELL, V97, P161
[2]   Anti-inflammatory actions of glucocorticoids: molecular mechanisms [J].
Barnes, PJ .
CLINICAL SCIENCE, 1998, 94 (06) :557-572
[3]   New glucocorticosteroids with an improved therapeutic ratio? [J].
Belvisi, MG ;
Brown, TJ ;
Wicks, S ;
Foster, ML .
PULMONARY PHARMACOLOGY & THERAPEUTICS, 2001, 14 (03) :221-227
[4]   Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition [J].
Bledsoe, RK ;
Montana, VG ;
Stanley, TB ;
Delves, CJ ;
Apolito, CJ ;
McKee, DD ;
Consler, TG ;
Parks, DJ ;
Stewart, EL ;
Willson, TM ;
Lambert, MH ;
Moore, JT ;
Pearce, KH ;
Xu, HE .
CELL, 2002, 110 (01) :93-105
[5]   CRYSTAL-STRUCTURE OF THE LIGAND-BINDING DOMAIN OF THE HUMAN NUCLEAR RECEPTOR RXR-ALPHA [J].
BOURGUET, W ;
RUFF, M ;
CHAMBON, P ;
GRONEMEYER, H ;
MORAS, D .
NATURE, 1995, 375 (6530) :377-382
[6]   Eplerenone - Cardiovascular protection [J].
Brown, NJ .
CIRCULATION, 2003, 107 (19) :2512-2518
[7]   Selective estrogen receptor modulators [J].
Bryant H.U. .
Reviews in Endocrine and Metabolic Disorders, 2002, 3 (3) :231-241
[8]   Molecular basis of agonism and antagonism in the oestrogen receptor [J].
Brzozowski, AM ;
Pike, ACW ;
Dauter, Z ;
Hubbard, RE ;
Bonn, T ;
Engstrom, O ;
Ohman, L ;
Greene, GL ;
Gustafsson, JA ;
Carlquist, M .
NATURE, 1997, 389 (6652) :753-758
[9]   Evaluation of ligand-dependent changes in AR structure using peptide probes [J].
Chang, CY ;
McDonnell, DP .
MOLECULAR ENDOCRINOLOGY, 2002, 16 (04) :647-660
[10]   Hierarchical affinities and a bipartite interaction model for estrogen receptor isoforms and full-length steroid receptor coactivator (SRC/p160) family members [J].
Cheskis, BJ ;
McKenna, NJ ;
Wong, CW ;
Wong, JM ;
Komm, B ;
Lyttle, CR ;
O'Malley, BW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (15) :13271-13277