Non-structural protein 3 macrodomain (Mac1) (Mac1)

The SARS-CoV-2 non-structural protein 3 macrodomain (Mac1), historically referred to as ADP-ribose phosphatase (ADRP), is a highly conserved viral enzyme essential for the pathogenesis of COVID-19 [1, 6]. It primarily functions as a mono-ADP-ribosylhydrolase, which catalyzes the removal of mono-ADP-ribose (MAR) modifications from host proteins [2, 4]. These modifications are typically added by host ADP-ribosyltransferases (PARPs) as a critical component of the innate immune response to viral infection [6, 16]. By reversing these modifications, Mac1 effectively antagonizes the host's interferon-mediated antiviral signaling, facilitating viral replication and immune evasion [5, 9]. Consequently, Mac1 has emerged as a significant therapeutic target, with research focusing on small-molecule inhibitors to restore the host's natural defenses [2, 16]. Experimental inhibitors such as AVI-4206 have demonstrated the ability to reduce viral replication and improve survival in animal models by potentiating the innate immune response [5, 9]. However, challenges remain regarding the translation of in vitro potency to cellular efficacy and the potential for off-target effects on human macrodomains [4, 8].

Other names

ADP-ribose phosphataseADRPADP-ribose-1''-phosphataseX-domainnsp3-Mac1SARS-CoV-2 macrodomainMacroD-type macrodomain

Inhibition of ADP-ribosylhydrolase activity to prevent the removal of antiviral ADP-ribose modifications from host proteins, thereby restoring the innate immune response.