Potent Protease Inhibitors of Highly Pathogenic Lagoviruses: Rabbit Hemorrhagic Disease Virus and European Brown Hare Syndrome Virus.
Potent Protease Inhibitors of Highly Pathogenic Lagoviruses: Rabbit Hemorrhagic Disease Virus and European Brown Hare Syndrome Virus.
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DOI：
10.1128/spectrum.00142-22
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发表时间：
2022-08-31
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
兔出血症（RHD）和欧洲褐兔综合征（EBHS）是由杯状病毒科兔瘟病毒引起的高度接触性传染病。这些传染病与高死亡率有关，并严重威胁到家养和野生兔子和野兔，包括濒临灭绝的物种，如河岸刷兔（Sylvilagus bachmani riparius）。在美国，在2020年春季之前，仅报告了RHD的孤立病例。然而，2020年4月在新墨西哥州意外报告了由GI.2/兔出血症病毒（RHDV）2/B引起的RHD，随后已蔓延至美国多个州，感染了野兔和野兔，使RHD极有可能在美国成为地方病。兔病毒编码一种3C样蛋白酶（3CLpro），这是病毒复制所必需的，也是抗病毒药物开发的一个有前途的靶点。我们之前已经产生了3CLpro抑制剂的集中小分子文库，并证明了一些蛋白酶抑制剂对编码3CLpro的病毒（包括杯状病毒和冠状病毒）的体外效力和体内功效。在这里，我们报告了酶和细胞为基础的测定GI. 1c/RHDV，重组GI. 3 P-GI.2（RHDV 2/B），和GII. 1/欧洲棕兔综合征病毒（EBHSV）的3CLpro的发展，以及有效的兔病毒3CLpro抑制剂，包括GC 376，正在开发的猫传染性腹膜炎的蛋白酶抑制剂的鉴定。此外，3CLpro和抑制剂的构效关系研究和同源性建模显示，兔病毒3CLpro与其他杯状病毒3CLpro具有相似的抑制结构要求。兔出血症（RHD）和欧洲褐兔综合征（EBHS）是影响兔形目动物的病毒性疾病，具有重大的经济和生态影响。风湿性心脏病疫苗是可用的，但针对这些病毒感染的特异性抗病毒治疗将是对当前控制措施的有价值的补充。兔病毒编码3C样蛋白酶（3CLpro），这是病毒复制所必需的，也是抗病毒药物发现的一个有吸引力的靶点。我们已经筛选并鉴定了在基于酶和细胞的测定中阻断兔病毒3CLpro的有效小分子抑制剂。我们的研究结果表明，这些化合物有潜力进一步发展为兔病毒的抗病毒药物。
Rabbit hemorrhagic disease (RHD) and European brown hare syndrome (EBHS) are highly contagious diseases caused by lagoviruses in the Caliciviridae family. These infectious diseases are associated with high mortality and a serious threat to domesticated and wild rabbits and hares, including endangered species such as riparian brush rabbits (Sylvilagus bachmani riparius). In the United States (U.S.), only isolated cases of RHD had been reported until Spring 2020. However, RHD caused by GI.2/rabbit hemorrhagic disease virus (RHDV)2/b was unexpectedly reported in April 2020 in New Mexico and has subsequently spread to several U.S. states, infecting wild rabbits and hares and making it highly likely that RHD will become endemic in the U.S. Vaccines are available for RHD; however, there is no specific treatment for this disease. Lagoviruses encode a 3C-like protease (3CLpro), which is essential for virus replication and a promising target for antiviral drug development. We have previously generated focused small-molecule libraries of 3CLpro inhibitors and demonstrated the in vitro potency and in vivo efficacy of some protease inhibitors against viruses encoding 3CLpro, including caliciviruses and coronaviruses. Here, we report the development of the enzyme and cell-based assays for the 3CLpro of GI.1c/RHDV, recombinant GI.3P-GI.2 (RHDV2/b), and GII.1/European brown hare syndrome virus (EBHSV) as well as the identification of potent lagovirus 3CLpro inhibitors, including GC376, a protease inhibitor being developed for feline infectious peritonitis. In addition, structure-activity relationship study and homology modeling of the 3CLpro and inhibitors revealed that lagovirus 3CLpro share similar structural requirements for inhibition with other calicivirus 3CLpro. IMPORTANCE Rabbit hemorrhagic disease (RHD) and European brown hare syndrome (EBHS) are viral diseases that affect lagomorphs with significant economic and ecological impacts. RHD vaccines are available, but specific antiviral treatment for these viral infections would be a valuable addition to the current control measures. Lagoviruses encode 3C-like protease (3CLpro), which is essential for virus replication and an attractive target for antiviral drug discovery. We have screened and identified potent small-molecule inhibitors that block lagovirus 3CLpro in the enzyme- and cell-based assays. Our results suggest that these compounds have the potential for further development as antiviral drugs for lagoviruses.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
14.9
作者：
Letunic I;Bork P
通讯作者：
Bork P
影响因子：
5.4
作者：
Kim, Yunjeong;Shivanna, Vinay;Chang, Kyeong-Ok
通讯作者：
Chang, Kyeong-Ok
影响因子：
5.4
作者：
Kim, Yunjeong;Lovell, Scott;Chang, Kyeong-Ok
通讯作者：
Chang, Kyeong-Ok