通过优化S'亚位点结合实现高选择性的基于机制的丝氨酸蛋白酶抑制剂
Mechanism-based inhibitors of serine proteases with high selectivity through optimization of S' subsite binding.
作者信息
Li Yi, Dou Dengfeng, He Guijia, Lushington Gerald H, Groutas William C
机构信息
Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
出版信息
Bioorg Med Chem. 2009 May 15;17(10):3536-42. doi: 10.1016/j.bmc.2009.04.011. Epub 2009 Apr 12.
Abstract
A series of mechanism-based inhibitors designed to interact with the S' subsites of serine proteases was synthesized and their inhibitory activity toward the closely-related serine proteases human neutrophil elastase (HNE) and proteinase 3 (PR 3) was investigated. The compounds were found to be time-dependent inhibitors of HNE and were devoid of any inhibitory activity toward PR 3. The results suggest that highly selective inhibitors of serine proteases whose primary substrate specificity and active sites are similar can be identified by exploiting differences in their S' subsites. The best inhibitor (compound 16) had a k(inact)/K(I) value of 4580 M(-1)s(-1).
摘要
合成了一系列旨在与丝氨酸蛋白酶的 S' 亚位点相互作用的基于机制的抑制剂，并研究了它们对密切相关的丝氨酸蛋白酶人中性粒细胞弹性蛋白酶（HNE）和蛋白酶 3（PR 3）的抑制活性。发现这些化合物是 HNE 的时间依赖性抑制剂，对 PR 3 没有任何抑制活性。结果表明，通过利用其 S' 亚位点的差异，可以鉴定出主要底物特异性和活性位点相似的丝氨酸蛋白酶的高选择性抑制剂。最佳抑制剂（化合物 16）的 k(inact)/K(I) 值为 4580 M(-1)s(-1)。
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本文引用的文献
1
X-ray snapshot of the mechanism of inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives.
J Med Chem. 2008 Apr 10;51(7):2003-8. doi: 10.1021/jm700966p. Epub 2008 Mar 5.
2
Epithelial responses to oxidative stress in chronic obstructive pulmonary disease: lessons from expression profiling.
Am J Respir Crit Care Med. 2007 Mar 15;175(6):527-8. doi: 10.1164/rccm.200612-1821ED.
3
The challenges of chronic obstructive pulmonary diseases (COPD)--a perspective.
COPD. 2005 Mar;2(1):177-84. doi: 10.1081/copd-200050676.
4
Leukocyte navigation mechanisms as targets in airway diseases.
Drug Discov Today. 2006 Oct;11(19-20):866-79. doi: 10.1016/j.drudis.2006.08.008. Epub 2006 Sep 7.
5
Neutrophil serine proteases: specific regulators of inflammation.
Nat Rev Immunol. 2006 Jul;6(7):541-50. doi: 10.1038/nri1841.
6
Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema.
Respir Res. 2006 Mar 30;7(1):53. doi: 10.1186/1465-9921-7-53.
7
Inspection of the binding sites of proteinase3 for the design of a highly specific substrate.
J Med Chem. 2006 Feb 23;49(4):1248-60. doi: 10.1021/jm051018t.
8
Pathogenesis of chronic obstructive pulmonary disease.
Proc Am Thorac Soc. 2005;2(4):258-66; discussion 290-1. doi: 10.1513/pats.200504-045SR.
9
Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease.
Proc Am Thorac Soc. 2005;2(1):50-60. doi: 10.1513/pats.200411-056SF.
10
COPD: current therapeutic interventions and future approaches.
Eur Respir J. 2005 Jun;25(6):1084-106. doi: 10.1183/09031936.05.00139104.
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