The Design and Generation of Unique Proteolysis-Targeting Chimeras (PROTACs) for Targeting Coronaviruses

In the aftermath of the COVID-19 pandemic, it has become clear that the rapid development of antiviral therapeutics is critical in the response to emerging pathogens. As new variants of SARS-CoV-2 emerge that confer resistance to vaccines and pharmaceutical agents, the need to create unique antiviral strategies that explore alternative mechanisms for combatting viral diseases has arisen. One such strategy that has expanded over the last several decades is the use of "PROteolysis-TArgeting Chimeras" or PROTACs as a means of Targeted Protein Degradation (TPD). With the use of a PROTAC, proteins critical in the viral replication cycle including structural proteins and host-cell proteins can be made the targets of TPD, and small molecules can be designed as an antiviral to facilitate their ubiquitination and subsequent degradation. Our group has begun research into the use of a bioPROTAC, an alternative PROTAC modality where proteins can be re-engineered as E3 ubiquitin ligases and offering several advantages over traditional PROTAC designs. Here, we present the use of a bioPROTAC based on the Spike protein from SARS-CoV-2 to target key proteins that the virus needs. So far, we have shown this bioPROTAC is effective in targeting critical proteins of SARS-CoV-2, and we are now testing this in live virus conditions. We also believe this bioPROTAC could have added benefits as a preventative treatment or vaccine, and plan to study its potential to trigger immune protection. Additionally, we are working on another PROTAC targeting the protein MGLL, a serine hydrolase critical for the life cycle of viruses such as Hepatitis C and HCoV-229E, a common cold virus. We are proposing studies on an MGLL PROTAC to show this strategy can be broadly applied to other viruses.