Lee Eui Seung, Lee Won Gil, Yun Soo-Hyeon, Rho Seong Hwan, Im Isak, Yang Sung Tae, Sellamuthu Saravanan, Lee Yong Jae, Kwon Sun Jae, Park Ohkmae K, Jeon Eun-Seok, Park Woo Jin, Kim Yong-Chul
Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
Biochem Biophys Res Commun. 2007 Jun 22;358(1):7-11. doi: 10.1016/j.bbrc.2007.03.208. Epub 2007 Apr 20.
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.
柯萨奇病毒B3（CVB3）3C蛋白酶（3CP）在病毒复制周期中发挥着重要作用，因此，它为治疗由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与人类鼻病毒（HRV）3CP具有高度的氨基酸序列相似性。对这两种3CP的比较建模揭示了一个显著的区别；在HRV 3CP中界定S2'口袋的Asn残基在CVB3 3CP中被Tyr残基取代。AG7088是一种有效的HRV 3CP抑制剂，通过用各种预测优先与CVB3 3CP的S2'口袋中的Tyr残基相互作用的疏水芳香环取代P2'位置的乙基进行修饰。所得衍生物对CVB3 3CP的抑制活性显著增加。此外，其中一种衍生物在体外有效抑制了CVB3的增殖。
