Rutgers scientists are currently researching a protein structure that could lead to a potential coronavirus (COVID-19) treatment. Stephen K. Burley, University professor and Henry Rutgers chair, said research on the 2003 severe acute respiratory syndrome (SARS) coronavirus outbreak could contribute to the current outbreak.
Burley is currently one of the directors of the Protein Data Bank (PDB), which is based at Rutgers and has other centers globally. This system allows for the upload and study of 3D structures of molecules such as proteins and nucleic acid.
At the end of January, a 3D structure of a key enzyme of the coronavirus was deposited into the PDB. Burley said this structure could have implications in terms of the virus’ function and ultimately treatment possibilities.
“When there is an emerging disease, researchers spend a lot of time turning resources trying to figure out the shape. If you know the shape, you can start to develop drugs and vaccines that will interact with the molecule,” said Christine Zardecki, the deputy director of outreach and education at the PDB.
Burley said the coronavirus is a piece of RNA that codes for a polyprotein. The role of this newly discovered enzyme is to cut the polyprotein in three key places. He said having this information opens the doors to further research that can be carried out to determine the small molecules a drug might target, in order to give more information on how the “fit” works, which could better maximize the effects of a drug.
“(The) 3D structures can be used as starting points for structure-guided drug discovery campaigns that seek to tailor the fit between the small molecule drug and the target proteins. The better the fit, the more potent the drug (meaning lower patient dosing) and better the fit the more selective the drug (meaning fewer side effects due to binding unwanted off target proteins),” Burley said.
Using the 3D structure, developing a drug which binds to an active site on the enzyme could block other molecules from binding or lead to a change in the enzyme’s shape, in both cases preventing the virus from carrying out its regular functions needed for survival.
“There may well be approved drugs or investigational agents in the later stage clinical trials that will prove effective against COVID-19,” Burley said. “That would be the best outcome — to identify a therapeutic agent known to be safe that will work for individuals infected with COVID-19. But we aren’t there yet, by any means.”
In 2003, SARS, another coronavirus strain, started in China and spread globally. The World Health Organization reported a total of 8,098 people worldwide became sick during the 2003 outbreak and 774 died, according to the Centers for Disease Control and Prevention (CDC). At the time, research was conducted on the structures that contributed to the virus’ functioning and discoveries were made, Burley said.
“The 3D structure of the SARS-CoV Main Protease was determined in 2003 and deposited to the open-access Protein Data Bank. The SARS-CoV and COVID-19 Main Proteases are 96 percent identical in amino acid sequence and the 3D structures of their active sites (where effective drugs would bind) are identical. Had a decision been made in 2003, while the SARS crisis was waning, to invest in the discovery and development of an anti-viral drug targeting the conserved coronavirus main Proteases, we would be having a very different conversation today,” Burley said.
Burley said there had been opportunities to work on developing a treatment that have not been seen through. Instead, individuals were quarantined and eventually the virus seemed to disappear.
Years later, in 2012, another strain of the coronavirus, Middle East Respiratory Syndrome, developed in the Middle East. The outbreak did not last long but had a mortality rate of 58 percent in infected individuals, according to the CDC. No course of treatment was put in place then either.
“Making vaccines and drug developments takes months and years … Making the structure available makes things go faster but we’re not going to solve this in a week,” Zardecki said.
As of today, there have been approximately 95,000 cases of the coronavirus and approximately 3,200 deaths. Research on the virus’s protein structure, at Rutgers and beyond, will continue until a successful treatment is implemented.