The search for inhibitors of macrodomains for targeting the readers and erasers of mono-ADP-ribosylation.

Macrodomains are evolutionarily conserved structural elements. Many macrodomains feature as binding modules of ADP-ribose, thus participating in the recognition and removal of mono- and poly-ADP-ribosylation. Macrodomains are involved in the regulation of a variety of physiological processes and represent valuable therapeutic targets. Moreover, as part of the nonstructural proteins of certain viruses, macrodomains are also pivotal for viral replication and pathogenesis. Thus, targeting viral macrodomains with inhibitors is considered to be a promising antiviral intervention. In this review, we summarize our current understanding of human and viral macrodomains that are related to mono-ADP-ribosylation, with emphasis on the search for inhibitors. The advances summarized here will be helpful for the design of macrodomain-specific agents for therapeutic and diagnostic applications.