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Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential

DOI: 10.1098/rsob.200237 DOI Help

Authors: Johannes Gregor Matthias Rack (University of Oxford) , Valentina Zorzini (University of Oxford) , Zihan Zhu (University of Oxford) , Marion Schuller (University of Oxford) , Dragana Ahel (University of Oxford) , Ivan Ahel (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Open Biology , VOL 10

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 27001

Open Access Open Access

Abstract: 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.

Journal Keywords: coronavirus, X domain, antiviral poly(ADP-ribosyl)polymerases, non-structural protein 3, (ADP-ribosyl)hydrolase, alphavirus

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography


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