By Sarah Carey and Doug Bennett
A new study by University of Florida researchers aims to identify a drug or drugs that can potentially be used to prevent and/or treat infection with COVID-19 by interfering with a known behavior of the virus — the way it binds to its cellular receptor, facilitating transmission to the respiratory system.
The receptor — angiotensin-converting enzyme-2, or ACE2 — serves as the vehicle through which the virus invades human cells, specifically those found in the respiratory tract and lungs, previous research has shown. Spike proteins cover the surface of the virus, also known as SARS-CoV-2, forming the “crown” that gives coronaviruses their name. The virus uses these spikes to attach to respiratory system cells that express ACE2.
The UF team plans to screen seven over-the-counter drugs approved by the U.S. Food and Drug Administration over a six-month period to assess their viability as candidates.
“Essentially, we are trying to block entry of the virus into airway cells that we culture,” said Leah Reznikov, Ph.D., an assistant professor of physiological sciences in the UF College of Veterinary Medicine and principal investigator on the study. Her laboratory focuses on the human airway and its response to noxious stimuli.
One of several projects approved in May by the UF Clinical and Translational Science Institute’s Rapid-Response Translational Research Funding initiative, the effort builds on previous research conducted by Reznikov’s co-investigator David Ostrov, Ph.D., an associate professor in the UF College of Medicine’s department of pathology, immunology and laboratory medicine, and others.
That earlier work investigated molecules that were predicted to interfere with SARS-CoV, another virus in the coronavirus family, and showed promising results, Reznikov said.
“In one study, they did find a decrease in viral entry,” she said. “This provides evidence that our rationale and approach to finding molecules that might be beneficial in COVID-19 is sound.”
The researchers plan to use a safe, modified virus that contains the SARS-CoV-2 surface glycoprotein and therefore cannot cause disease like native SARS-CoV-2. Using computer modeling, Ostrov’s team identified drug candidates predicted to interfere with the binding of SARS-CoV-2 spike protein with ACE2. They then validated these drug candidates for their ability to bind to ACE2 by examining ACE2 activity.
The team next plans to use Reznikov’s modified virus, which expresses the SARS-CoV-2 spike protein, to see if the drug candidates prevent viral entry.
“If we find that one or more of these drugs prevent viral entry, or disrupt the interaction of the surface glycoprotein with ACE2, then we will more thoroughly test the drugs for their ability to disrupt viral entry of native SARS-CoV-2,” Reznikov said.
Scientists are learning more about how the coronavirus interacts with ACE2, a normal human protein that has effects on cardiac function as well as on controlling blood pressure, Ostrov said.
“ACE2 is a flexible molecule shaped like a Pac-Man,” he said. “Sometimes the mouth is open, sometimes it is closed. The coronavirus binds the open mouth form of ACE2. Drugs that bind and stabilize the closed mouth form of ACE2 make it less likely to serve as a receptor for the virus.”
The researchers hope their efforts will lead to the identification of approved drugs, preferably over-the-counter drugs, which inhibit virus infection when used at a safe dose.
“If a promising drug candidate is identified and FDA-approved, then the approval process to use in humans for a new indication should be greatly expedited,” Reznikov said.