New anti-viral drugs for the treatment of the common cold
New anti-viral drugs for the treatment of the common cold
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DOI：
10.1016/j.bmc.2007.12.030
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发表时间：
2008-03-15
影响因子：
3.5
通讯作者：
Cazzolla, Nicola
中科院分区：
文献类型：
--
作者：
Maugeri, Caterina;Alisi, Maria A.;Cazzolla, Nicola
人鼻病毒（HRV）是成人和儿童普通感冒最重要的病原体。 HRV 是一种单链正义 RNA 病毒，尽管不同血清型之间具有高度保守性，但病毒蛋白酶 3C 与哺乳动物蛋白酶的序列比对显示没有同源性。因此，蛋白酶3C是开发抗HRV药物的最佳靶标。在目前的工作中，我们研究了针对 HRV 蛋白酶 3C 的新型潜在可逆抑制剂的设计、合成和开发。对 HRV2 蛋白酶 3C 结晶结构的对接研究使我们设计并合成了一系列能够充当底物类似物的 3,5 二取代苯甲酰胺。我们还开发了 1,3,5 三取代苯甲酰胺，其中芳环上的芳香族取代使我们研究了 pi-pi 相互作用对蛋白酶 3C 抑制剂复合物稳定的重要性。所有结构均测试了对 HRV14 蛋白酶 3C 的酶抑制作用。结果突出了化合物 13、14 和 20 的抑制活性（10 μM 时分别为 91%、81% 和 85%），后者对 HRV-14 的 ID50（抑制 50% 病毒细胞病变效应的剂量）= 25 μg/ml。 (C) 2007 Elsevier Ltd. 保留所有权利。
Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents. In the present work we investigated the design, the synthesis and the development of new potential reversible inhibitors against HRV protease 3C. Docking studies on the crystallized structure of HRV2 protease 3C led us to the design and the synthesis of a series of 3,5 disubstituted benzamides able to act as analogues of the substrate. We also developed 1,3,5 tri-substituted benzamides where aromatic substitutions on the aryl ring led us to investigate the importance of pi-pi interaction on the stabilization of protease 3C-inhibitor complex. All structures were tested for enzymatic inhibition on HRV14 protease 3C. Results highlighted the inhibitory activity of compounds 13, 14, and 20 (91%, 81%, and 85% at 10 mu M, respectively), with the latter exhibiting an ID50 (dose that inhibits 50% of the viral cytopathic effect) on HRV-14 = 25 mu g/ml. (C) 2007 Elsevier Ltd. All rights reserved.