PLpro inhibitors are primarily investigated for their antiviral properties, especially in targeting coronaviruses such as SARS-CoV-2. These compounds work by blocking the activity of the papain-like protease (PLpro), a key viral enzyme involved in processing viral polyproteins necessary for replication. By inhibiting PLpro, these agents disrupt the virus's ability to mature and propagate within host cells. In addition to impairing viral replication, PLpro inhibitors also help preserve the host’s innate immune response. The PLpro enzyme is known to interfere with cellular signaling pathways that trigger antiviral defenses, particularly by removing ubiquitin and ISG15 modifications from host proteins. Inhibiting PLpro allows these immune pathways to remain active, enhancing the body’s ability to fight the infection. Due to their dual mechanism—direct antiviral action and immune modulation—PLpro inhibitors are being explored as potential broad-spectrum therapeutics against multiple coronaviruses. They are a focus in the development of oral antiviral drugs, aiming to provide effective treatment options for early-stage infections and reduce disease progression.