Development of COVID-2019 main protease inhibitors as potential antivirals against the 2019 coronavirus.
Coronaviruses are associated with a variety of human diseases ranging from the common cold to new and serious conditions such as Severe Acute Respiratory Syndrome (SARS), which emerged in 2002, Middle Eastern Respiratory Syndrome (MERS), first reported in 2012, and a recent and still growing outbreak of COVID-19, caused by the coronavirus SARS-CoV-2. MERS and SARS together claimed over 1600 lives, and the death toll of COVID‑19 recently passed 1300 and is growing rapidly. It is currently unclear if the COVID‑19 outbreak can be contained, with some estimates of potential fatalities reaching as high as 50 million. There is currently no approved treatment for any coronavirus, although clinical trials of the Gilead compound Remdesivir are currently underway and there is some optimism that it may be effective against SARS-CoV-2. Nevertheless, there is an urgent need for additional potential SARS-CoV-2 therapeutics, as the success of Remdesivir is far from assured. We are proposing to use a combination of computer calculations and laboratory testing to rapidly identify and validate molecules that block an enzyme that is essential to the virus. The targeted enzyme, known as 3CLpro, is responsible for processing viral proteins into their active forms. A detailed 3D structure of the SARS-CoV-2 3CLpro enzyme was recently solved, and this provides enough information to identify chemical structures of molecules that are likely to block its action, through a procedure known as virtual screening. We will synthesize promising compounds and test them against the purified enzyme using a technique known as Isothermal Titration Calorimetry (ITC). Our team has a proven track record of using virtual screening and ITC to generate potent inhibitors of enzymes similar to 3CLpro. Molecules we identify are likely to prevent the virus from replicating and would have high value as new potential treatments for COVID‑19 that could be used alone or in combination with other therapies