While there are few things to be thankful about with respect to the current pandemic, we can be grateful, at least, that it is not a hemorrhagic fever virus like Ebola or Marburg, which have mortality rates ranging from 25% to 90%. Moreover, there are currently no drugs to prevent infection from these filoviruses, making them exponentially more difficult to treat. Previous research uncovered that a few small drug molecules could block filoviruses from infecting cells by occupying a single site on a glycoprotein in the virus. However, now, investigators at the University of Illinois Chicago (UIC) have recently identified a second site on the filovirus glycoprotein to which small drug molecules can bind and prevent infection.
Findings from the new study—published recently in PLOS Pathogens through an article titled, “Evidence for distinct mechanisms of small molecule inhibitors of filoviral entry”— shows that small drug molecules blocking both glycoprotein sites may be more effective and reduce the risk of side effects.
“We need to identify how these filoviruses get into cells as a means to help us identify or develop drugs that can prevent infection,” explained senior study investigator Lijun Rong, PhD, a UIC professor of microbiology and immunology at the College of Medicine. “Even though at the moment Ebola and Marburg are not in the news that often, having drugs in our arsenal in case of a flare-up is invaluable. These viruses also mutate constantly, so having a better understanding of how they work will let us develop next-generation viral inhibitors.”
Rong and his collaborators identified the second glycoprotein binding site by pairing the virus with hundreds of different small drug molecules thought to possibly have an effect on viral entry into cells. Several of the drugs were able to prevent viral access.
Through a series of experiments using molecular, biophysical, and structural experimental techniques, they were able to look more closely at how these drugs were interacting with the virus. They found that the drugs were binding to a previously unknown site on the viral surface glycoprotein required for cell infection.
“We provided evidence that toremifene and other small molecule entry inhibitors have at least three distinct mechanisms of action and lay the groundwork for future development of anti-filoviral agents,” the authors wrote. “The three mechanisms identified here include: (1) direct binding to the internal fusion loop region of Ebolavirus (EBOV) glycoprotein (GP); (2) the HR2 domain is likely the main binding site for Marburgvirus GP inhibitors and a secondary binding site for some EBOV GP inhibitors; (3) lysosome trapping of GP inhibitors increases drug exposure in the lysosome and further improves the viral inhibition. Importantly, small molecules targeting different domains on GP are synergistic in inhibiting EBOV entry suggesting these two mechanisms of action are distinct.”
“The good news is that there are already drugs approved by the FDA that can bind to the new site we identified,” Rong concluded. “If we can give drugs that bind to the site we newly identified and the site previously identified, it can help prevent viral infection with lower doses of each drug. Interfering with both sites on the viral surface glycoprotein, it also reduces the chances of the glycoprotein mutating to the point that it escapes the effect of the drug combination and is able to infect cells once again.”