CAS, a division of the American Chemical Society, Columbus, Ohio 43210, United States.
ACS Infect Dis. 2022 Mar 11;8(3):422-432. doi: 10.1021/acsinfecdis.2c00031. Epub 2022 Feb 23.
Since the beginning of the COVID-19 pandemic caused by SARS-CoV-2, millions of patients have been diagnosed and many of them have died from the disease worldwide. The identification of novel therapeutic targets are of utmost significance for prevention and treatment of COVID-19. SARS-CoV-2 is a single-stranded RNA virus with a 30 kb genome packaged into a membrane-enveloped virion, transcribing several tens of proteins. The belief that the amino acid sequence of proteins determines their 3D structure which, in turn, determines their function has been a central principle of molecular biology for a long time. Recently, it has been increasingly realized, however, that there is a large group of proteins that lack a fixed or ordered 3D structure, yet they exhibit important biological activities─so-called intrinsically disordered proteins and protein regions (IDPs/IDRs). Disordered regions in viral proteins are generally associated with viral infectivity and pathogenicity because they endow the viral proteins the ability to easily and promiscuously bind to host proteins; therefore, the proteome of SARS-CoV-2 has been thoroughly examined for intrinsic disorder. It has been recognized that, in fact, the SARS-CoV-2 proteome exhibits significant levels of structural order, with only the nucleocapsid (N) structural protein and two of the nonstructural proteins being highly disordered. The spike (S) protein of SARS-CoV-2 exhibits significant levels of structural order, yet its predicted percentage of intrinsic disorder is still higher than that of the spike protein of SARS-CoV. Noteworthy, however, even though IDPs/IDRs are not common in the SARS-CoV-2 proteome, the existing ones play major roles in the functioning and virulence of the virus and are thus promising drug targets for rational antiviral drug design. Presented here is a COVID-19 perspective on the intrinsically disordered proteins, summarizing recent results on the SARS-CoV-2 proteome disorder features, their physiological and pathological relevance, and their prominence as prospective drug target sites.
自 SARS-CoV-2 引起的 COVID-19 大流行开始以来，全球已诊断出数百万例患者，其中许多患者死于该疾病。确定新的治疗靶标对于 COVID-19 的预防和治疗至关重要。SARS-CoV-2 是一种单链 RNA 病毒，其基因组为 30 kb，包装在膜包被的病毒粒子中，转录数十种蛋白质。很长一段时间以来，人们一直认为蛋白质的氨基酸序列决定其 3D 结构，而 3D 结构又决定其功能，这是分子生物学的一个核心原则。然而，最近越来越多的人认识到，有一大类蛋白质缺乏固定或有序的 3D 结构，但它们具有重要的生物学活性，即所谓的无规则卷曲蛋白质和蛋白质区域（IDPs/IDRs）。病毒蛋白中的无序区域通常与病毒的感染力和致病性有关，因为它们使病毒蛋白能够轻易且随意地与宿主蛋白结合；因此，对 SARS-CoV-2 的蛋白质组进行了彻底的无序性检查。人们认识到，事实上，SARS-CoV-2 的蛋白质组表现出显著的结构有序性，只有核衣壳（N）结构蛋白和两种非结构蛋白高度无序。SARS-CoV-2 的刺突（S）蛋白表现出显著的结构有序性，但它的预测无规则卷曲百分比仍然高于 SARS-CoV 的刺突蛋白。然而，值得注意的是，即使 IDPs/IDRs 在 SARS-CoV-2 的蛋白质组中并不常见，但现有的 IDPs/IDRs 在病毒的功能和毒力中发挥着重要作用，因此是合理的抗病毒药物设计的有前途的药物靶标。本文从 COVID-19 的角度介绍了无规则卷曲蛋白质，总结了 SARS-CoV-2 蛋白质组无序特征的最新结果、它们的生理和病理相关性，以及它们作为有前途的药物靶标位点的突出地位。
