By Cara Penquite | Bond LSC
Vaccines were the light at the end of the tunnel throughout the COVID-19 pandemic, but virus mutations threaten to extinguish hope of a quick end to the pandemic. Kamlendra Singh turns towards antivirals as the next step.
“There will be a time we will find an antiviral which will be very difficult for the virus to mutate [and avoid],” Singh said, “That’s what we are after.”
The Singh lab studied COVID-19 antiviral compounds that prevent binding between the virus and host cells with help from Siddappa Byrareddy, professor and vice-chair of research in the Department of Pharmacology Experimental Neuroscience at the University of Nebraska Medical Center (UNMC). The first COVID-19 antiviral compound Singh’s team discovered during their in a preliminary study conducted in mouse models, has been filed for a patent while they continue to search for the antivirals that target different proteins of the virus. These compounds would prevent the virus from entering cells even after exposure to the virus.
The antiviral compound disrupts the interaction between the ACE2 receptor on the surface of host cells and the spike protein on the virus so the virus cannot infect cells. ACE2 acts as a doorway into the cell where COVID-19 binds, enters and takes over the cell. Once inside, the virus hijacks the cell and uses it to create more virus. Additionally, the virus releases its genome into the host cells, activating cell defense mechanisms which can be more dangerous than the infection itself.
While vaccines prepare the immune system to fight off COVID-19, Singh’s antivirals simply block this doorway.
“The very first thing was to find the compound that can inhibit viral entry because it is the first step of the infection,” Singh said. “If you can block the very first step then you can block everything else.”
Vaccines act as a practice round for the body where the immune response learns which antibodies are effective against the virus. But when the virus mutates, antibodies built up from vaccination or prior infection may be less effective against the mutated virus.
The antiviral compounds discovered by Singh and his team do not have this problem since they bind to the host cell’s receptors where few mutations occur. Additionally, the compounds can change their shape in response to those mutations that may occur.
“We call it ‘wiggling and jiggling,’” Singh said. “The compound has the capability to change it’s shape conformation.”
This ability to change shape is not unique to COVID-19 antivirals. Drawing on previous experience working on HIV antivirals, Singh explains that shape changing properties are common in molecules with single bonds between their component atoms.
“If you have a single bond somewhere, then they can change or they can reorient and bind someplace,” Singh said.
Singh believes antivirals may be the key to fighting COVID-19 even with emerging mutants. While vaccines mitigated COVID-19 rates and hospitalizations, they also might have played a role in the creation of new mutants.
“It’s probably too early to say, but it looks like these variants are probably evolving under the pressure of antibodies,” Singh said. “Those antibodies may have been induced by either direct infusions giving the antibodies [to patients], or they may have been induced by other vaccines or by previous infection.”
While viruses also mutate under the pressure of antivirals, Singh hopes to find an antiviral that is difficult for the virus to avoid through mutation.
“We have been working on developing a better compound using the compounds we discovered, and we have found one more compound that has at least 10 times better efficacy against [SARS-Cov-2],” Singh said.
Kamlendra Singh is a research assistant professor of molecular microbiology and immunology and assistant director of the Molecular Interactions Core at Bond LSC. Singh wished to express his sincere gratitude to Prof. Byrareddy (University of Nebraska Medical School). Without their collaboration, the discovery of the antiviral compounds would not be possible. Singh is also thankful to two students – Saathvik Kannan (a Hickman High School student) and Austin (a Mizzou undergrad). Without the help of these two talented young scientists, the research would not have been so successful. Finally, Singh mentioned that the support from the Bond Life Sciences Center has been extremely valuable in his research.