PDF(Pubmed)
Abstract：
The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35% and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of SARS-CoV-2, MERS-CoV and other main proteases. Nirmatrelvir inhibited several of these proteases, whereas ensitrelvir was less broadly active. To simulate nirmatrelvir\'s clinical use against MERS-CoV and subsequent resistance development, we applied a safe, surrogate virus-based system. Using the surrogate virus, we previously selected hallmark mutations of SARS-CoV-2-Mpro, such as T21I, M49L, S144A, E166A/K/V and L167F. In the current study, we selected a pool of MERS-CoV-Mpro mutants, characterized the resistance and modelled the steric effect of catalytic site mutants S142G, S142R, S147Y and A171S.
摘要：
中东呼吸综合征冠状病毒（MERS-CoV）是一种流行病，2012年在沙特阿拉伯首次报告了人畜共生病原体。MERS-CoV有可能与其他冠状病毒突变或重组，从而获得在人类中有效传播并成为大流行的能力。其高达35％的高死亡率和缺乏有效的靶向治疗需要开发针对该病原体的抗病毒药物。自从SARS-CoV-2大流行开始以来，广泛的研究集中在鉴定用于治疗SARS-CoV-2的蛋白酶抑制剂。因此，我们的目的是评估这些蛋白酶抑制剂是否是对抗MERS-CoV的可行选择。为此,我们使用以前建立的蛋白酶测定法来定量抑制SARS-CoV-2,MERS-CoV和其他主要蛋白酶.Nirmatrelvir抑制了这些蛋白酶中的几种，而ensitrelvir的活性较低。为了模拟nirmatrelvir对MERS-CoV的临床使用和随后的耐药性发展，我们用了一个保险箱，代理基于病毒的系统。使用替代病毒，我们之前选择了SARS-CoV-2-Mpro的标志性突变，例如T21I，M49L,S144A,E166A/K/V和L167F。在目前的研究中,我们选择了一组MERS-CoV-Mpro突变体,表征了催化位点突变体S142G的抗性并模拟了空间效应，S142R,S147Y和A171S。
