Defining the druggability of viral macrodomains in coronaviruses and alphaviruses.

Abstract

Viral macrodomains are ADP-ribosylhydrolases encoded within the nonstructural proteins of coronaviruses and alphaviruses-2 RNA virus families with pandemic potential. Genetic studies demonstrate that ADP-ribose binding and ADP-ribosylhydrolase activity are critical for replication in alphaviruses and select coronaviruses, such as Middle East respiratory syndrome coronavirus and murine hepatitis virus. In contrast, for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, this domain primarily enhances in vivo fitness by modulating the innate immune response, establishing the macrodomain as a validated antiviral target. Structure-guided and high-throughput efforts have identified selective inhibitors for SARS-CoV-2 and, more recently, early-stage inhibitors of the alphavirus chikungunya virus. Both exploit a conserved active-site architecture that organizes ligand recognition into adenine, phosphate, ribose, and oxyanion subsites. Despite screening of extensive chemical libraries, inhibitor discovery has repeatedly converged on adenine-anchored scaffolds requiring polar engagement of the oxyanion region to achieve potency. This convergence defines a structurally confined druggable corridor but reveals a persistent permeability-potency tradeoff imposed by the polarity required for catalytic engagement. Cross-family comparisons further demonstrate localized divergence that shapes selectivity and constrains straightforward scaffold portability. Here, we synthesize structural, biochemical, and antiviral advances across SARS-CoV-2 and chikungunya virus, define the current boundaries of macrodomain chemical space, and delineate the chemical and biological constraints that now govern translation of catalytic inhibition into predictable antiviral efficacy. SIGNIFICANCE STATEMENT: Viral macrodomains have emerged as compelling antiviral targets in 2 pandemic-potential virus families, coronaviruses and alphaviruses, owing to their conservation and role in virulence. This review defines the chemical space and druggability of the severe acute respiratory syndrome coronavirus 2 and chikungunya virus macrodomains and the structural and biological constraints that must be overcome to translate catalytic inhibition into next-generation antivirals.

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