Coronaviruses (CoVs) can cause highly prevalent diseases in humans and animals. The fatal
outbreak of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome
(MERS) highlights the threat posed by this unique virus subfamily. However, no specific drugs
have been approved to treat CoV-associated diseases to date. The CoV proteases, which play
pivotal roles in viral gene expression and replication through a highly complex cascade involving
the proteolytic processing of replicase polyproteins, are attractive targets for drug design. This
review summarizes the recent advances in biological and structural studies, together with the
development of inhibitors targeting CoV proteases, particularly main proteases (Mpros), which could
help develop effective treatments to prevent CoV infection.