Jain Rajendra P, Pettersson Hanna I, Zhang Jianmin, Aull Katherine D, Fortin Pascal D, Huitema Carly, Eltis Lindsay D, Parrish Jonathan C, James Michael N G, Wishart David S, Vederas John C
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
J Med Chem. 2004 Dec 2;47(25):6113-6. doi: 10.1021/jm0494873.
The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the alpha-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC(50) values ranging from 0.60 to 70 microM.
严重急性呼吸综合征（SARS）冠状病毒的3C样蛋白酶（3CL(pro)）是针对这种病毒感染进行基于结构的药物设计的关键靶点。该酶识别在P1位点带有谷氨酰胺残基的肽底物。合成了一系列在α位带有邻苯二甲酰肼基的酮谷氨酰胺类似物，并作为针对SARS 3CL(pro)的可逆抑制剂进行测试。将三肽（Ac-Val-Thr-Leu）连接到这些基于谷氨酰胺的“弹头”上产生了显著更好的抑制剂（4a-c，8a-d），其IC(50)值范围为0.60至70 microM。
