Viral macrodomains possess the ability to counteract host ADP-ribosylation, a post-translational modification implicated in the creation of an antiviral environment via immune response regulation. This brought them into focus as promising therapeutic targets, albeit the close homology to some of the human macrodomains raised concerns regarding potential cross-reactivity and adverse effects for the host. Here, we evaluate the structure and function of the macrodomain of SARS-CoV-2, the causative agent of COVID-19. We show that it can antagonize ADP-ribosylation by PARP14, a cellular (ADP-ribosyl)transferase necessary for the restriction of coronaviral infections. Furthermore, our structural studies together with ligand modelling revealed the structural basis for poly(ADP-ribose) binding and hydrolysis, an emerging new aspect of viral macrodomain biology. These new insights were used in an extensive evolutionary analysis aimed at evaluating the druggability of viral macrodomains not only from the Coronaviridae but also Togaviridae and Iridoviridae genera (causing diseases such as Chikungunya and infectious spleen and kidney necrosis virus disease, respectively). We found that they contain conserved features, distinct from their human counterparts, which may be exploited during drug design.

病毒大结构域具有对抗宿主 ADP 核糖基化的能力，这是一种翻译后修饰，涉及通过免疫反应调节创建抗病毒环境。这使它们成为有希望的治疗靶点，尽管它们与一些人类宏结构域的密切同源性引起了人们对潜在交叉反应性和对宿主的不利影响的担忧。在这里，我们评估了 COVID-19 病原体 SARS-CoV-2 宏结构域的结构和功能。我们证明它可以拮抗 PARP14 的 ADP-核糖基化，PARP14 是限制冠状病毒感染所必需的细胞 (ADP-核糖基) 转移酶。此外，我们的结构研究和配体建模揭示了聚（ADP-核糖）结合和水解的结构基础，这是病毒大结构域生物学的一个新兴的新方面。这些新见解被用于广泛的进化分析，旨在评估病毒大结构域的成药性，不仅来自冠状病毒科，还包括披膜病毒科和虹彩病毒科（分别引起基孔肯雅热和传染性脾肾坏死病毒病等疾病）。我们发现它们包含与人类对应物不同的保守特征，这些特征可以在药物设计过程中加以利用。