Inhibitors of SARS-CoV-2 PLpro

The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now similar to 30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.

Automated summary

The emergence of SARS-CoV-2 and the COVID-19 pandemic have emphasized the importance of urgent collaboration and building on existing research for rapid vaccine development. However, even highly vaccinated countries still face surges in cases and hospitalizations. Therefore, the development of antiviral treatments remains a top priority to prevent hospitalization and death, and ultimately end the pandemic caused by SARS-CoV-2. The focus of this review is on the essential papain-like protease (PLpro) domain within the nsp3 protein of SARS-CoV-2, which plays a crucial role in viral processing and immune response inhibition. Small molecule inhibitors of PLpro have shown promising results in reducing viral loads, making PLpro an excellent target for next generation antivirals. The review discusses ongoing efforts in designing PLpro inhibitors and optimizing existing compounds for more effective treatment options.