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

Autor: Rack, Johannes Gregor Matthias, Zorzini, Valentina, Zhu, Zihan, Schuller, Marion, Ahel, Dragana, Ahel, Ivan
Jazyk: angličtina
Rok vydání: 2020
Předmět:
X domain
Druggability
coronavirus
Viral Nonstructural Proteins
medicine.disease_cause
Homology (biology)
RESPIRATORY SYNDROME CORONAVIRUS
antiviral poly(adp-ribosyl)polymerases
alphavirus
Coronaviridae
lcsh:QH301-705.5
Coronavirus
0303 health sciences
biology
General Neuroscience
030302 biochemistry & molecular biology
Recombinant Proteins
Molecular Docking Simulation
(ADP-ribosyl)hydrolase
Poly(ADP-ribose) Polymerases
HOST-RANGE
Life Sciences & Biomedicine
Research Article
Protein Binding
Iridoviridae
MACRO DOMAIN
Biochemistry & Molecular Biology
REVERSIBLE ADP-RIBOSYLATION
Immunology
NSP3
INHIBITION
Computational biology
Alphavirus
x domain
General Biochemistry
Genetics and Molecular Biology
Evolution
Molecular
non-structural protein 3
03 medical and health sciences
ADP-Ribosylation
Protein Domains
medicine
Humans
030304 developmental biology
Adenosine Diphosphate Ribose
Binding Sites
Science & Technology
antiviral poly(ADP-ribosyl)polymerases
CHIKUNGUNYA VIRUS
Research
RNA-Dependent RNA Polymerase
biology.organism_classification
ALPHAVIRUS
lcsh:Biology (General)
Togaviridae
REPLICATION
RNA
(adp-ribosyl)hydrolase
Kidney necrosis
Zdroj: Open Biology
Open Biology, Vol 10, Iss 11 (2020)
Popis: 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.
Databáze: OpenAIRE
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