Lobiuc Andrei, Șterbuleac Daniel, Sturdza Olga, Dimian Mihai, Covasa Mihai
Department of Biomedical Sciences, College of Medicine and Biological Sciences, "Ștefan cel Mare" University of Suceava, Str. Universității 13, 720229 Suceava, Romania.
Division of Infectious Diseases, Suceava County Regional Emergency Hospital, 720229 Suceava, Romania.
Biology (Basel). 2021 Dec 5;10(12):1276. doi: 10.3390/biology10121276.
The ongoing COVID-19 pandemic follows an unpredictable evolution, driven by both host-related factors such as mobility, vaccination status, and comorbidities and by pathogen-related ones. The pathogenicity of its causative agent, SARS-CoV-2 virus, relates to the functions of the proteins synthesized intracellularly, as guided by viral RNA. These functions are constantly altered through mutations resulting in increased virulence, infectivity, and antibody-evasion abilities. Well-characterized mutations in the spike protein, such as D614G, N439K, Δ69-70, E484K, or N501Y, are currently defining specific variants; however, some less studied mutations outside the spike region, such as p. 3691 in NSP6, p. 9659 in ORF-10, 8782C > T in ORF-1ab, or 28144T > C in ORF-8, have been proposed for altering SARS-CoV-2 virulence and pathogenicity. Therefore, in this study, we focused on A105V mutation of SARS-CoV-2 ORF7a accessory protein, which has been associated with severe COVID-19 clinical manifestation. Molecular dynamics and computational structural analyses revealed that this mutation differentially alters ORF7a dynamics, suggesting a gain-of-function role that may explain its role in the severe form of COVID-19 disease.
当前的新冠疫情发展态势难以预测，这是由宿主相关因素（如流动性、疫苗接种状况和合并症）以及病原体相关因素共同驱动的。其病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒的致病性与病毒RNA指导下在细胞内合成的蛋白质功能有关。这些功能通过突变不断改变，导致毒力、传染性和抗体逃避能力增强。刺突蛋白中特征明确的突变，如D614G、N439K、Δ69-70、E484K或N501Y，目前正在定义特定的变体；然而，刺突区域外一些研究较少的突变，如非结构蛋白6（NSP6）中的p. 3691、开放阅读框10（ORF-10）中的p. 9659、开放阅读框1ab（ORF-1ab）中的8782C>T或开放阅读框8（ORF-8）中的28144T>C，已被提出可改变SARS-CoV-2的毒力和致病性。因此，在本研究中，我们聚焦于SARS-CoV-2 ORF7a辅助蛋白的A105V突变，该突变与严重的新冠临床表现相关。分子动力学和计算结构分析表明，这种突变以不同方式改变了ORF7a的动力学，提示其功能获得作用，这可能解释了它在严重形式的新冠疾病中的作用。
