Coronaviruses. Coronaviruses belong to a highly diverse family of enveloped positive-sense singlestranded RNA (+ssRNA) viruses which are capable of infecting mammals, including humans, and birds. They can cause respiratory tract infections ranging from mild symptoms such as nasal congestion to lethal symptoms such as pneumonia in humans. Human coronaviruses, such as HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 only cause seasonal and usually mild respiratory tract infections generally known as the "common cold". Since the discovery of the first human coronaviruses (HCoV-229E and HCoV-OC43) in the 1960s, the medicinal chemistry community has not paid much attention to these viruses as they were considered to be non-lethal. However, as the severe acute respiratory syndrome (SARS) in 2002, Middle East respiratory syndrome (MERS) in 2012, and coronavirus disease 2019 (COVID-19) appeared in humans and caused fatal respiratory illnesses, public health concerns for these PL pro inhibitor GRL0617, which was also found to inhibit SARS-CoV-2 PL pro . A crystal structure (PDB code: 7CJM) revealed that this compound does not bind near the catalytic cysteine but rather at the entrance of the tunnel to the catalytic site (Figure ). Similarly, another SARS-CoV-1 PL pro (IC50 of 5 μM) and MERS PL pro (IC50 of 4.4 μM) inhibitor, 6-thioguanine (6-TG), was found to inhibit SARS-CoV-2 PL pro in cell lines. An alternative strategy is to modify the substrate peptide sequence into an inhibitor. The best tetrapeptide substrates were identified by Rut and co-workers and these peptides were converted into inhibitors like VIR251, which binds covalently to the catalytic cysteine (Figures and) albeit with micromolar potency at best. It was not until late 2021 that submicromolar PL pro inhibitors were reported. These non-covalent inhibitors, analogues of GRL0617, were crystallized (e.g., PDB ID: 7LLF). Recently, more analogues of GRL0617 have been investigated. Researchers replaced the methyl substituent of GRL0617 with a peptidomimetic linker and an electrophile to react with Cys111 in the PL pro active site (Figure ). With the fumarate ester being an electrophile, this hybrid inhibitor's potency has reached 0.094 μM.