Drug-like molecules offer a promising treatment for COVID-19

A team of researchers at the University of Georgia have demonstrated that a series of small molecules, such as drugs, can block the activity of the major SARS-CoV-2 protein, providing a promising path to new COVID-19 therapies.

The team, led by Scott Pegan, head of the UGA Drug Discovery Center, was the first team to evaluate the SARS-CoV-2 protein PLpro, which is known to be essential in other areas. Coronavirus Both because of its replication and its ability to suppress the immune function of the host.

The SARS-CoV-2 PLpro behaved differently than its predecessor, which caused the outbreak of SARS in 2003. Specifically, our data suggest that SARS-CoV-2 PLpro is less effective in its immunosuppressive role. This may be one of the underlying reasons why the current virus is not as deadly as the 2003 outbreak virus“

Scott Pegan, Professor, Department of Pharmacy and Biomedical Sciences, University of Georgia

The COVID-19 pandemic affects more lives around the world than the 2002-03 outbreak of SARS, but its mortality rate is lower based on available numbers in early June .

After the SARS outbreak, the World Health Organization reported 8,098 cases and 774 deaths, with a mortality rate of almost 10%. According to the Johns Hopkins University COVID-19 dashboard on June 3, there were 6,435,453 confirmed cases and 382,093 deaths worldwide, with a mortality rate of almost 6%.

From an evolutionary perspective, viruses aren’t as lethal to hosts as Pegan says. The 2003 SARS was particularly deadly.

“The COVID-19 virus infects but does not generate the heat before it is transmitted, so it’s about how pathogenic factors like PLpro are naturally modified by the virus to give it a better chance. , There’s a lot of focus, to co-exist with us,” he said.

“Obviously, we don’t want it to co-exist, but COVID-19 seems to have solved the Goldilocks paradox of being at the right place, at the right time, and at the right infection level.”

Pegan, in collaboration with UGA scientists David Crich, Ralph Tripp, and Brian Cummings, sought to find inhibitors designed to knock out PLpro and stop viral replication.

It started with a series of compounds discovered 12 years ago and shown to be effective against SARS, but development has been shortened because SARS did not recur.

“Obviously, the current coronavirus will probably be with us for some time now, and if not this is probably another type of coronavirus,” Pegan said. “These compounds are a good starting point for therapeutic development. They have all the properties one would normally want in a drug and have a history of not being considered toxic.”

These compounds, naphthalene-based PLpro inhibitors, have been shown to be effective in arresting and replicating SARS-CoV-2 PLpro activity. They provide a potential rapid development path for generating PLpro targeted therapies for use against SARS-CoV-2.

“The kind of small molecule we’re developing is part of the first specifically designed for this coronavirus protease,” Pegan said. “So far, most therapeutic studies on SARS have targeted another virulence factor, C3Lpro.

This is a great start with another target. Our hope is that this can be a starting point for creating a drug that can be obtained in front of the Food and Drug Administration. “

Four UGA labs, including students, brought their expertise to the project. Pegan’s lab uses modeling techniques to identify the differences between the 2003 outbreak PLpro and the current outbreak, reveal the weaknesses of SARS-CoV-2 PLpro, and suggest potential inhibitors of testing. did.

Drug chemist Professor David Crich and Georgia Research Alliance and David Chu Eminent Scholar in Drug Design provide guidance for understanding the attributes of inhibitors and work on the synthesis of new compounds with improved properties. is.

Testing of compounds against the virus was led by Ralph Tripp, a veterinary university professor of infectious disease, a prominent scholar of vaccine and therapeutics at the Georgia Research Alliance, a specialist in respiratory viruses and related diseases.

Professor and head of pharmaceuticals and biomedicine, Brian Cummings, took up toxicology and confirmed that the compounds tested reliably killed their intended target without toxic effects on the host.

The paper of the team is published online in ACS ACS Infectious Diseases, published by the American Chemical Society. In addition to Pegan, Crich, and Tripp, co-authors are Robert Jeff Hogan, a professor of veterinary bioscience and diagnostic imaging. Jakerin Murray, research scientist. Graduate students Brendan Freitas and Ian Durie. I’m Jaron Longo and Holden Miller in the department.