USP18 Inhibitors

USP18, also known as Ubiquitin-specific protease 18, is a crucial regulator of the interferon (IFN) signaling pathway and plays a significant role in modulating innate immune responses to viral infections and other pathogens. One of its primary functions is to negatively regulate the type I interferon (IFN-I) signaling pathway by deconjugating the ubiquitin-like protein ISG15 from target proteins. ISG15ylation, the process of attaching ISG15 to target proteins, is induced upon IFN-I stimulation and is involved in antiviral defense mechanisms. USP18 acts as a deISGylating enzyme, removing ISG15 from target proteins and thereby attenuating the antiviral effects of IFN-I signaling. Additionally, USP18 has been implicated in the regulation of other cellular processes, including cell proliferation, apoptosis, and autophagy, highlighting its diverse roles beyond the immune system.

Inhibition of USP18 can be achieved through various mechanisms, primarily aimed at disrupting its enzymatic activity or interfering with its interaction with other proteins within the IFN signaling pathway. One approach involves the development of small molecule inhibitors that specifically target the catalytic site of USP18, inhibiting its deISGylating activity and thereby enhancing the antiviral response mediated by IFN-I signaling. Another strategy for inhibiting USP18 involves the disruption of protein-protein interactions critical for its function. By blocking the interaction between USP18 and its binding partners, such as IFNα/β receptor subunits or ISG15-modified proteins, it is possible to inhibit USP18-mediated negative regulation of IFN-I signaling. Additionally, modulation of USP18 expression levels or subcellular localization may also represent avenues for inhibiting its activity and enhancing the innate immune response against viral infections. Overall, understanding the mechanisms of USP18 inhibition provides insights into its role in immune regulation and may offer new opportunities for combating viral infections and other immune-related diseases.