Cutting edge small molecule reagents targeting key proteins and mechanisms of coronavirus infection.
Like any virus, the Coronavirus SARS-CoV-2 causes Coronavirus Disease 2019 (COVID-19) by hijacking host cell mechanisms. At the host cell surface, ACE2 and TMPRSS2 are necessary for infection. ACE2 and TMPRSS2 are cell-membrane-associated proteases expressed in the lungs and other organs. Like its relative SARS-CoV, SARS-CoV-2 uses ACE2 as a docking protein, then depends on TMPRSS2 to cleave and prime its S protein, enabling the virus to enter the cell.
Once the virus has access to the cellular interior, it utilizes cellular machinery to produce other enzymes and proteins encoded by the viral RNA genome. Two other essential enzymes are the virus' own Main Protease (Mpro, 3CLpro), and Papain-Like Protease (PLpro, Nsp3). Many other viral and host proteins also play key or subsidiary roles in infection.
MERS-CoV and SARS-CoV (responsible for the outbreaks of Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome in 2012 and 2003, respectively) have very high similarity to SARS-CoV-2. Therefore, prior and current research on these viruses is also of great benefit to understanding SARS-CoV-2 and has led to identification of many inhibitors of Coronavirus infection and replication.
Researchers and drug discovery scientists are applying two methods of approach in the small molecule arena. The first is repurposing existing compounds; the second is discovering new small molecules that specifically inhibit SARS-CoV-2.