Kim Yunjeong, Shivanna Vinay, Narayanan Sanjeev, Prior Allan M, Weerasekara Sahani, Hua Duy H, Kankanamalage Anushka C Galasiti, Groutas William C, Chang Kyeong-Ok
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USA
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USA.
J Virol. 2015 May;89(9):4942-50. doi: 10.1128/JVI.03688-14. Epub 2015 Feb 18.
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.
Feline 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.
猫传染性腹膜炎和强毒性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，是猫科动物中死亡率很高的重要传染病。虽然FCoV和FCV分别属于两个不同的病毒科，即冠状病毒科和杯状病毒科，但它们在复制过程中都依赖病毒3C样蛋白酶（3CLpro）。由于3CLpro在这些病毒中功能和结构保守且对病毒复制至关重要，因此3CLpro被认为是设计针对这些不同且极为重要的病毒感染的具有广谱活性的抗病毒药物的潜在靶点。然而，此前尚未鉴定出针对FCoV和FCV的3CLpro酶的小分子抑制剂。在本研究中已合成了靶向3CLpro的肽基化合物衍生物，并评估了它们对FCoV和FCV的活性。已鉴定并讨论了显示出具有宽安全范围的强效双重抗病毒活性的化合物结构。此外，使用冠状病毒感染小鼠模型评估了3CLpro抑制剂的体内疗效。在感染嗜肝冠状病毒甲型鼠肝炎病毒（murine hepatitis virus A59）的小鼠中腹腔注射两种3CLpro抑制剂，与对照组相比，肝脏中的病毒滴度和病理损伤显著降低。这些结果表明，本文所述的一系列3CLpro抑制剂可能有潜力进一步开发成为针对家养和野生猫中这些重要病毒的治疗药物。本研究为设计具有更广泛抗病毒活性的抗病毒药物提供了关于3CLpro结构与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，而强毒性全身性猫杯状病毒（vs-FCV）在猫中引起一种尚无预防或治疗措施的高度致命疾病。这些属于不同病毒科的不同病毒的基因组编码一种结构和功能保守的3C样蛋白酶（3CLpro），它是广谱抗病毒药物开发的潜在靶点。然而，此前尚无研究报道针对这些病毒具有活性的抗病毒药物设计的结构平台，也没有关于3CLpro抑制剂在实验动物中抗冠状病毒感染疗效的研究。在本研究中，我们探索了3CLpro抑制剂衍生物的构效关系，并鉴定出对这些病毒具有强效双重活性的抑制剂。此外，在感染鼠冠状病毒的小鼠中证明了3CLpro抑制剂的疗效。总体而言，我们的研究首次深入了解了抗FIPV和抗FCV药物开发的结构平台。
