Image: The discovery of a small molecule in the research lab of Bradley McConnell, professor of pharmacology at the University of Houston College of Pharmacy, could well be the emergence of new drugs that could shorten the course of the coronavirus. see more
Photo credit: University of Houston
The discovery of a small molecule in the research lab of Bradley McConnell, a professor of pharmacology at the University of Houston College of Pharmacy, could well be the birth of new drugs that could shorten the course of the SARS-CoV-2 virus. Unlike Paxlovid, Pfizer’s antiviral drug, which is only useful for the first three days after symptoms appear, this potential new drug could shorten the course of the virus upon exposure.
“Neutralizing small molecules can provide immediate protection against viral infections and are therefore appropriate for people of all ages and may be particularly useful in high-risk populations and immunocompromised individuals who do not typically produce enough antibodies after vaccination,” McConnell said in Biomedicines. “This exciting new small molecule drug candidate has the potential to be developed into an alternative drug treatment for COVID-19.”
Discovery of the molecule began at the height of the pandemic, when students at McConnell’s lab were working from home and the idea arose that maybe a tiny molecule could affect the virus. The team verified 1,509,984 feature-rich connections in the UH Research Computing Data Core, home of the Hewlett Packard Enterprise Data Science Institute.
The team was looking for a molecule that could disrupt the interaction between the spike protein, found on the outside of the coronavirus, and its human target for entering human cells, the ACE2 protein.
“Our team is excited about the discovery of a small molecule therapeutic that inhibits the interaction between the spike protein of the COVID-19 virus and the ACE2 receptor of the infected individual,” said McConnell. “We are grateful that the university has the powerful computing power on campus to drive our work so effectively. This is a discovery that could ultimately impact many lives.”
McConnell’s team includes Arfaxad Reyes-Alcaraz, Hanan Qasim, Elizabeth Merlinsky, Tasneem Islam and Bryan Medina of UH College of Pharmacy; Robert J. Schwartz, John W. Craft, Jr. from the UH Department of Biology and Biochemistry; and Glenn Fox, Rogers State University in Oklahoma.
During the experimental phase, the team selected the top 15 molecules that disrupted the interaction between the spike protein and the ACE2 receptor. Molecular dynamics simulations showed that some of the compounds from these libraries had favorable interactions with the cleavage site of the ACE receptor binding domain of the spike protein, resulting in potential neutralization of SARS-CoV-2 infection, and one particular molecule rose to the Tip: CD04872SC, which formed the closest connection.
“We were able to observe experimentally that CD04872SC also inhibits the infection of the SARS-CoV-2 variants Delta and Omicron,” says Reyes-Alcaraz, the first author of the study.
“To demonstrate the binding between CD04872SC and the spike proteins of each variant, we performed a thermal shift assay that measures changes in thermal denaturation temperature and serves as an indicator of the stability of a protein under different conditions, e.g. when it’s attached to a drug, pH, ionic strength, or sequence mutation,” said Craft, associate professor in the Department of Biology and Biochemistry.
It’s a medical discovery whose time has come.
The SARS-CoV-2 virus and its variants Delta and Omicron remain a major threat to patients of all ages. The variants show how easily the virus can accommodate antigenic changes in its spike protein without loss of fitness.
“The Omicron variant has placed a particular strain on healthcare systems around the world. Therefore, there is an urgent need to identify effective antiviral agents to combat this infectious disease,” McConnell said.
Looking ahead, McConnell suggests further development of molecular derivatives and pre-clinical studies.
“This promising drug candidate should be developed into a family of derivatives that could be further refined, potentially leading to a more effective and less expensive alternative to expensive neutralizing treatments,” McConnell said.
article title
A small molecule that neutralizes infection with SARS-CoV-2 and its most contagious variants, Delta and Omicron, in vitro
Article publication date
March 15, 2023
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