Broad-Spectrum Inhibitors against 3C-Like Proteases of Feline Coronaviruses and Feline Caliciviruses
Broad-Spectrum Inhibitors against 3C-Like Proteases of Feline Coronaviruses and Feline Caliciviruses
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DOI：
10.1128/jvi.03688-14
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发表时间：
2015-05-01
影响因子：
5.4
通讯作者：
Chang, Kyeong-Ok
中科院分区：
文献类型：
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作者：
Kim, Yunjeong;Shivanna, Vinay;Chang, Kyeong-Ok
猫传染性腹膜炎和全身性杯状病毒感染分别由某些类型的猫冠状病毒(FCoV)和猫杯状病毒(FCV)引起，是猫科动物中病死率较高的重要传染病。虽然口蹄疫和口蹄疫属于两个不同的病毒家族，分别是冠状病毒科和杯状病毒科，但它们都依赖病毒3C样蛋白酶(3CLpro)进行复制。由于3CLpro在功能和结构上在这些病毒中是保守的，对病毒复制是必不可少的，3CLpro被认为是设计具有广谱活性的抗病毒药物的潜在靶点，以对抗这些独特和高度重要的病毒感染。然而，针对FCoV和FCV的3CLPro酶的小分子抑制剂还没有被鉴定出来。本研究合成了以3CLPro为靶标的多肽类化合物，并对其抗口蹄疫和口蹄疫的活性进行了评价。鉴定并讨论了具有强大的双重抗病毒活性的化合物，并对其进行了讨论。此外，利用冠状病毒感染的小鼠模型评估了3CLPro抑制剂的体内疗效。与对照组相比，在感染小鼠肝炎病毒A59(一种嗜肝冠状病毒)的小鼠体内注射两种3CLPro抑制剂后，病毒滴度和肝脏病理损害显著降低。这些结果表明，本文所描述的系列3CLPro抑制剂可能有潜力进一步开发为针对这些重要病毒的家猫和野猫的治疗药物。这项研究为设计具有更广泛抗病毒活性的抗病毒药物提供了对3CLpro结构和功能关系的重要见解。猫传染性腹膜炎病毒(FIPV)是幼猫死亡的主要原因，而强毒全身性猫杯状病毒(VS-FCV)可引起猫的一种高度致命的疾病，目前尚无预防或治疗措施。这些不同的病毒属于不同的病毒家族，它们的基因组编码一种结构和功能保守的3C样蛋白酶(3CLpro)，这是开发广谱抗病毒药物的潜在靶点。然而，此前还没有研究报道具有抗这些病毒活性的抗病毒药物的结构平台，也没有关于3CLPro抑制剂在实验动物中对抗冠状病毒感染的有效性的研究。在这项研究中，我们探索了3CLPro抑制剂衍生物的构效关系，并确定了对这些病毒具有强大双重活性的抑制剂。此外，3CLPro抑制剂在感染小鼠冠状病毒的小鼠身上也证明了有效性。总体而言，我们的研究为抗FIPV和抗FCV药物开发提供了第一个结构性平台。
Feline infectious peritonitis and virulent, systemic calicivirus infection are caused by certain types of feline coronaviruses (FCoVs) and feline caliciviruses (FCVs), respectively, and are important infectious diseases with high fatality rates in members of the Felidae family. While FCoV and FCV belong to two distinct virus families, the Coronaviridae and the Caliciviridae, respectively, they share a dependence on viral 3C-like protease (3CLpro) for their replication. Since 3CLpro is functionally and structurally conserved among these viruses and essential for viral replication, 3CLpro is considered a potential target for the design of antiviral drugs with broad-spectrum activities against these distinct and highly important viral infections. However, small-molecule inhibitors against the 3CLpro enzymes of FCoV and FCV have not been previously identified. In this study, derivatives of peptidyl compounds targeting 3CLpro were synthesized and evaluated for their activities against FCoV and FCV. The structures of compounds that showed potent dual antiviral activities with a wide margin of safety were identified and are discussed. Furthermore, the in vivo efficacy of 3CLpro inhibitors was evaluated using a mouse model of coronavirus infection. Intraperitoneal administration of two 3CLpro inhibitors in mice infected with murine hepatitis virus A59, a hepatotropic coronavirus, resulted in significant reductions in virus titers and pathological lesions in the liver compared to the findings for the controls. These results suggest that the series of 3CLpro inhibitors described here may have the potential to be further developed as therapeutic agents against these important viruses in domestic and wild cats. This study provides important insights into the structure and function relationships of 3CLpro for the design of antiviral drugs with broader antiviral activities.IMPORTANCEFeline infectious peritonitis virus (FIPV) is the leading cause of death in young cats, and virulent, systemic feline calicivirus (vs-FCV) causes a highly fatal disease in cats for which no preventive or therapeutic measure is available. The genomes of these distinct viruses, which belong to different virus families, encode a structurally and functionally conserved 3C-like protease (3CLpro) which is a potential target for broad-spectrum antiviral drug development. However, no studies have previously reported a structural platform for the design of antiviral drugs with activities against these viruses or on the efficacy of 3CLpro inhibitors against coronavirus infection in experimental animals. In this study, we explored the structure-activity relationships of the derivatives of 3CLpro inhibitors and identified inhibitors with potent dual activities against these viruses. In addition, the efficacy of the 3CLpro inhibitors was demonstrated in mice infected with a murine coronavirus. Overall, our study provides the first insight into a structural platform for anti-FIPV and anti-FCV drug development.