广谱对3 c蛋白酶抑制剂的猫科动物冠状病毒和猫杯状病毒。
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金正日Y, Shivanna V, Narayanan年代之前,Weerasekara年代,DH, Kankanamalage AC, Groutas WC, Chang KO
广谱对3 c蛋白酶抑制剂的猫科动物冠状病毒和猫杯状病毒。
J微生物学报。2015年5月,89 (9):4942 - 50。doi: 10.1128 / JVI.03688-14。Epub 2015年2月18日。
- PubMed ID
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25694593 (在PubMed]
- 文摘
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未标记的:猫传染性腹膜炎和毒性,系统性的杯状病毒感染是由某些类型的猫科动物冠状病毒(FCoVs)和猫杯状病毒(流量控制阀),分别是重要的传染病,死亡率高,猫科家族的成员。而FCoV和流量控制阀属于两个截然不同的病毒家族,Coronaviridae和Caliciviridae,分别,他们共享一个依赖病毒3 c蛋白酶(3 clpro)的复制。因为3 clpro功能和结构守恒在这些病毒和病毒复制所必需的,3 clpro被认为是一个潜在的目标与广谱抗病毒药物的设计活动对这些不同的和非常重要的病毒感染。然而,3 clpro酶的小分子抑制剂FCoV和流量控制阀还没有被发现。在这项研究中,肽基化合物的衍生品针对3 clpro合成和评估活动对FCoV和流量控制阀。化合物的结构显示的双重抗病毒活动与广泛的安全边际就被确定并进行了讨论。此外,3 clpro抑制剂的体内疗效评估使用冠状病毒感染的小鼠模型。腹腔内的两个3 clpro抑制剂对小鼠感染鼠肝炎病毒的事故,hepatotropic冠状病毒,导致病毒滴度和病理病变显著减少肝脏相比的结果控制。这些结果表明,这里描述的一系列3 clpro抑制剂有可能会进一步发展为治疗药物对这些重要的病毒在家养和野生的猫。这项研究提供了重要的见解的结构和功能关系3 clpro与更广泛的抗病毒抗病毒药物的设计活动。 IMPORTANCE: 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.
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