Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease.
Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease.
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DOI：
10.1016/j.antiviral.2012.11.005
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发表时间：
2013-02
影响因子：
7.6
通讯作者：
Chang KO
中科院分区：
文献类型：
--
作者：
Kim Y;Mandadapu SR;Groutas WC;Chang KO
猫传染性腹膜炎病毒(►)是一种猫致死性疾病的病原体。针对病毒3C/3CL的►酶抑制剂在细胞内对猫传染性腹膜炎病毒有明显的抑制作用。►将抑制剂的抗病毒效果与进入阻滞剂组织蛋白酶B的抑制剂进行比较。►这些抑制剂与组织蛋白酶B抑制剂在细胞内对FIPV有很强的协同作用。猫冠状病毒感染在国内外猫科动物中很常见，通常与轻度或无症状的肠炎有关；然而，猫传染性腹膜炎(FIP)是一种由猫传染性腹膜炎病毒(FIPV)引起的猫的致命疾病，FIPV是猫肠道冠状病毒(FECV)的变种。目前，尽管FIP作为幼猫死亡的主要感染性原因很重要，但还没有批准用于FIP的特定治疗方法。在复制过程中，冠状病毒产生病毒多蛋白，这些蛋白被病毒蛋白酶、主要的蛋白酶(类3C[3CL]酶)和类木瓜蛋白酶加工成成熟的蛋白。由于病毒多蛋白的裂解是病毒复制的关键步骤，因此阻断病毒蛋白水解酶是治疗干预的一个有吸引力的靶点。在此之前，我们曾报道过针对具有3C或3CL蛋白酶的病毒的广谱多肽抑制剂的产生。在这项研究中，我们进一步评估了肽类抑制剂对猫冠状病毒的抗病毒作用，并在细胞培养中研究了我们的蛋白酶抑制剂和组织蛋白酶B抑制剂(一种进入阻滞剂)对猫冠状病毒的相互作用。在此，我们报道了我们的化合物作为3CL蛋白酶的可逆竞争性抑制剂，有效地抑制猫冠状病毒的复制(EC50在纳摩尔范围内)，此外，组织蛋白酶B和3CL蛋白酶抑制剂的组合在细胞培养系统中导致了对猫冠状病毒的强烈协同作用。
► Feline infectious peritonitis virus (FIPV) is a causative agent of a fatal disease among cats. ► Protease inhibitors targeting virus 3C/3CL protease potently inhibited feline infectious peritonitis virus in cells. ► The antiviral effects of inhibitors were compared with a cathepsin B inhibitor, an entry blocker. ► The inhibitors exerted strong synergistic effects with a cathepsin B inhibitor against a FIPV in cells. Feline coronavirus infection is common among domestic and exotic felid species and usually associated with mild or asymptomatic enteritis; however, feline infectious peritonitis (FIP) is a fatal disease of cats that is caused by systemic infection with a feline infectious peritonitis virus (FIPV), a variant of feline enteric coronavirus (FECV). Currently, there is no specific treatment approved for FIP despite the importance of FIP as the leading infectious cause of death in young cats. During the replication process, coronavirus produces viral polyproteins that are processed into mature proteins by viral proteases, the main protease (3C-like [3CL] protease) and the papain-like protease. Since the cleavages of viral polyproteins are an essential step for virus replication, blockage of viral protease is an attractive target for therapeutic intervention. Previously, we reported the generation of broad-spectrum peptidyl inhibitors against viruses that possess a 3C or 3CL protease. In this study, we further evaluated the antiviral effects of the peptidyl inhibitors against feline coronaviruses, and investigated the interaction between our protease inhibitor and a cathepsin B inhibitor, an entry blocker, against a feline coronavirus in cell culture. Herein we report that our compounds behave as reversible, competitive inhibitors of 3CL protease, potently inhibited the replication of feline coronaviruses (EC50 in a nanomolar range) and, furthermore, combination of cathepsin B and 3CL protease inhibitors led to a strong synergistic interaction against feline coronaviruses in a cell culture system.
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冠状病毒主蛋白酶的结构揭示了甲over依蛋白酶折叠与额外的α-螺旋结构域的组合。
影响因子：
11.4
作者：
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通讯作者：
Hilgenfeld, Rolf
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影响因子：
3.8
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
Chang, Kyeong-Ok