Abstract：
Human coronaviruses are a group of pathogens that primarily cause respiratory and intestinal diseases. Infection can easily cause respiratory symptoms, as well as a variety of serious complications. There are several types of human coronaviruses, such as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, and SARS-CoV-2. The prevalence of COVID-19 has led to a growing focus on drug research against human coronaviruses. The main protease (Mpro) from human coronaviruses is a relatively conserved that controls viral replication. X77 was discovered to have extremely high inhibitory activity against SARS-CoV-2 Mpro through the use of computer-simulated docking. In this paper, we have resolved the crystal structure of the HCoV-NL63 Mpro complexed with X77 and analyzed their interaction in detail. This data provides essential information for solving their binding modes and their structural determinants. Then, we compared the binding modes of X77 with SARS-CoV-2 Mpro and HCoV-NL63 Mpro in detail. This study illustrates the structural basis of HCoV-NL63 Mpro binding to the inhibitor X77. The structural insights derived from this study will inform the development of new drugs with broad-spectrum resistance to human coronaviruses.
摘要：
人冠状病毒是一组主要引起呼吸道和肠道疾病的病原体。感染容易引起呼吸道症状,以及各种严重的并发症。有几种人类冠状病毒,比如SARS-CoV,MERS-CoV,HCoV-229E,HCoV-OC43、HCoV-NL63、HCoV-HKU1和SARS-CoV-2。COVID-19的流行导致人们越来越关注针对人类冠状病毒的药物研究。来自人冠状病毒的主要蛋白酶(Mpro)是相对保守的,其控制病毒复制。通过使用计算机模拟对接，发现X77对SARS-CoV-2Mpro具有极高的抑制活性。在本文中,我们已经解析了与X77络合的HCoV-NL63Mpro的晶体结构，并详细分析了它们的相互作用。该数据为解决其结合模式及其结构决定因素提供了必要的信息。然后，我们详细比较了X77与SARS-CoV-2Mpro和HCoV-NL63Mpro的结合模式。该研究说明了HCoV-NL63Mpro与抑制剂X77结合的结构基础。从这项研究中得出的结构见解将为开发对人类冠状病毒具有广谱抗性的新药提供信息。
