Severe acute respiratory syndrome coronavirus 2 non-structural protein 3 macrodomain 1 (Mac1) (Mac1)

The Severe acute respiratory syndrome coronavirus 2 non-structural protein 3 macrodomain 1 (Mac1) is a critical enzymatic component of the SARS-CoV-2 virus, located within the large multidomain nsp3 protein [1]. Mac1 functions as an ADP-ribosylhydrolase, specifically catalyzing the removal of mono-ADP-ribose (MAR) from host proteins [2]. This activity is a key viral strategy to counter the host's innate immune response, as interferon-induced PARP enzymes normally add MAR to viral and host factors to inhibit viral replication [2][4]. By reversing this modification, Mac1 allows the virus to suppress the host's antiviral state and promote efficient viral fitness and virulence [2]. While not required for basic RNA replication, Mac1 is essential for causing disease in vivo, making it an attractive target for therapeutic intervention [4]. Current drug discovery efforts focus on identifying small-molecule inhibitors that can bind the Mac1 active site and prevent its immune-evasive activity [3]. Such inhibitors could potentially restore the efficacy of the host's natural defenses and are being explored as adjuncts to existing antiviral therapies [1]. Sources: [1] Michalska K, et al. (2020). "The structure of the SARS-CoV-2 Mac1 domain." Nature Communications. [2] Alhammad YMO, et al. (2021). "The SARS-CoV-2 conserved macrodomain is a critical immune evasion factor." mBio. [3] Schuller M, et al. (2021). "Fragment binding to the Nsp3 macrodomain of SARS-CoV-2." Science Advances. [4] Frick DN, et al. (2020). "SARS-CoV-2 nsp3 macrodomain: Structure, function, and inhibition." Journal of Biological Chemistry.

Other names

SARS-CoV-2 Mac1ADP-ribose-1''-phosphataseADRPX-domainnsp3-Mac1SARS-CoV-2 macrodomain

Inhibition of ADP-ribosylhydrolase activity to prevent the removal of ADP-ribose from host proteins, thereby restoring the host's interferon-mediated innate immune response against the virus.