![]() ![]() Furthermore, PARP14 was shown to promote anti-inflammatory interleukin-4-mediated signalling pathways by activating STAT6-dependent gene expression and inhibiting STAT-1-dependent gene expression. While, for instance, the antiviral effect of PARP12 was shown to be achieved at least partially through the inhibition of protein translation and by promoting the ADP-ribosylation-dependent degradation of viral proteins, PARP9 provides a possibility of viral infection control in complex with DTX3L by targeting EMCV 3C protease for ubiquitination and degradation. ![]() The interferon (IFN) response triggered through viral infections thereby induces the gene expression of several PARP family members, i.e., PARP7 and PARPs 9–14, whose ADP-ribosylation signalling activity establishes an antiviral environment. Macrodomains are highly conserved domains found in all kingdoms of life and recognise ADP-ribosylation modifications on proteins and nucleic acids catalysed by poly(ADP-ribosyl)polymerases (PARPs). SARS-CoV-2 NSP3 features eight (out of 15) domains that exist in all known coronaviruses, including ubiquitin-like domains, PL2 pro, transmembrane regions, and a macrodomain (Mac1). NSP3 is thereby the largest multi-domain protein produced by coronaviruses and is itself an essential component of the replication and transcription complex. ![]() Moreover, the viral proteases, the main protease (M pro), and the papain-like protease 2 (PL2 pro), are inhibited by peptide analogues (e.g., nirmatrelvir) and small molecules to prevent the processing of two polypeptides into constituent viral non-structural proteins (NSP) required for viral replication. Thus, the RNA polymerase is targeted with nucleoside analogues (e.g., remdesivir or molnupiravir) to inhibit the genome replication and gene transcription of SARS-CoV-2. Proteins involved in the viral replication machinery are thereby in particular focus as drug targets. SARS-CoV-2 is characterised as an enveloped single-stranded positive sense RNA β-coronavirus whose genome encodes for 29 proteins essential for the viral life cycle and its modulation of host immune responses. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure–activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. ![]()
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