Development of potent inhibitors of the coxsackievirus 3C protease
Development of potent inhibitors of the coxsackievirus 3C protease
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DOI：
10.1016/j.bbrc.2007.03.208
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发表时间：
2007-06-22
影响因子：
3.1
通讯作者：
Kim, Yong-Chul
中科院分区：
文献类型：
--
作者：
Lee, Eui Seung;Lee, Won Gil;Kim, Yong-Chul
柯萨奇病毒 B3 (CVB3) 3C 蛋白酶 (3CP) 在病毒复制周期中发挥重要作用，因此为治疗 CVB3 感染引起的人类疾病提供了一个有吸引力的治疗靶点。 CVB3 3CP和人鼻病毒(HRV) 3CP具有高度的氨基酸序列相似性。这两个 3CP 的比较模型揭示了一个显着的区别： HRV 3CP 中描绘 S2' 口袋的 Asn 残基被 CVB3 3CP 中的 Tyr 残基取代。 AG7088 是 HRV 3CP 的有效抑制剂，通过用各种疏水芳环取代 P2' 位置的乙基进行修饰，预计这些芳环会优先与 CVB3 3CP S2' 口袋中的 Tyr 残基相互作用。所得衍生物对 CVB3 3CP 的抑制活性显着增加。此外，其中一种衍生物在体外有效抑制CVB3增殖。 (c) 2007 Elsevier Inc. 保留所有权利。
Coxsackievirus B3 (CVB3) 3C protease (3CP) plays essential roles in the viral replication cycle, and therefore, provides an attractive therapeutic target for treatment of human diseases caused by CVB3 infection. CVB3 3CP and human rhinovirus (HRV) 3CP have a high degree of amino acid sequence similarity. Comparative modeling of these two 3CPs revealed one prominent distinction; an Asn residue delineating the S2' pocket in HRV 3CP is replaced by a Tyr residue in CVB3 3CP. AG7088, a potent inhibitor of HRV 3CP, was modified by substitution of the ethyl group at the P2' position with various hydrophobic aromatic rings that are predicted to interact preferentially with the Tyr residue in the S2' pocket of CVB3 3CP. The resulting derivatives showed dramatically increased inhibitory activities against CVB3 3CP. In addition, one of the derivatives effectively inhibited the CVB3 proliferation in vitro. (c) 2007 Elsevier Inc. All rights reserved.