New studies from the Oak Ridge National Laboratory (ORNL) have found that several hepatitis C virus (HCV) drugs can inhibit the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, a crucial protein enzyme that enables the novel coronavirus to reproduce.

Blocking the protease from functioning is vital to stop the virus from spreading in patients with coronavirus 2019 (COVID-19), according to the study. The study was done in an effort to help quickly develop pharmaceutical treatments for COVID-19 by repurposing existing drugs known to effectively treat other viral diseases, according to the study authors.

"Currently, there are no inhibitors approved by the Food and Drug Administration that target the SARS-CoV-2 main protease," said ORNL lead author Daniel Kneller in a press release. "What we found is that hepatitis C drugs bind to and inhibit the coronavirus protease. This is an important first step in determining whether these drugs should be considered as potential repurposing candidates to treat COVID-19."

In the study, the researchers examined several well-known drug molecules for potential repurposing efforts, including leupeptin, a naturally occurring protease inhibitor, and 3 FDA-approved HCV protease inhibitors: telaprevir (Incivek), narlaprevir (Arlansa), and boceprevir (Victrelis).

Room temperature X-ray measurements were performed to build a 3-dimensional map that revealed how the atoms were arranged and where chemical bonds formed between the protease and the drug inhibitor molecules. The experiments yielded promising results for certain HCV drugs in their ability to bind and inhibit the SARS-CoV-2 main protease, particularly boceprevir and narlaprevir, according to the study authors.

Further, the researchers used vitro enzyme kinetics to better understand how well or how tightly the inhibitors bind to the protease. This technique enables researchers to study the protease and the inhibitor in a test tube to measure the inhibitor’s binding affinity, or compatibility, with the protease.

"What we're doing is laying the molecular foundation for these potential drug repurposing inhibitors by revealing their mode of action," said ORNL corresponding author Andrey Kovalevsky in a press release. "We show on a molecular level how they bind, where they bind, and what they're doing to the enzyme shape. And, with in vitro kinetics, we also know how well they bind. Each piece of information gets us one step closer to realizing how to stop the virus."

In addition, the study sheds light on a peculiar behavior of the protease’s ability to change or adapt its shape according to the size and structure of the inhibitor molecule it binds to. Since the pockets within the protease where a drug molecule would attach are highly flexible, the pockets can either open or close to an extent depending on the size of the drug molecules.

The study authors emphasized that more research, including clinical trials, is necessary to validate the drugs’ efficacy and safety as a COVID-19 treatment.

"The research suggests that hepatitis C inhibitors are worth thinking about as potential repurposing candidates. Immediately releasing our data allows the scientific community to start looking at the interactions between these inhibitors and the protease," said ORNL corresponding author Leighton Coates in a press release. "You can't design a drug without knowing how it works on a molecular level, and the data we're providing is exactly what developers need to design stronger, more tightly binding drugs for more effective treatments."

REFERENCE
X-ray study explores potential of hepatitis C drugs to treat COVID-19. EurekAlert! https://www.eurekalert.org/pub_releases/2020-11/drnl-xse111620.php. Published November 16, 2020. Accessed November 17, 2020.