Scientists discover novel series of SARS-CoV-2 mpro inhibitors for potential new COVID-19 treatments

Despite effective vaccines approved for use worldwide, COVID-19 continues to contribute to mortality and morbidity -- an issue compounded by the problems of vaccine & therapy access. However, the existing drug designs in use for COVID-19 therapy lend themselves to drug interactions and the risk of incomplete viral inhibition.

To address this problem, Salvino -- a medicinal chemist at Wistar -- led a drug discovery team with the goal of improving upon the existing Mpro inhibitor design, an approach to viral therapy that seeks to prevent both viral replication and mutation-based drug resistance by targeting a component of the virus that regulates its ability to spread. And because Mpro is not an easy-to-mutate biological feature like a spike protein, inhibiting Mpro can help retain antiviral effectiveness even between different variations.

The team used a drug discovery technique that applied an "acyloxymethyl ketone electrophilic warhead" -- in essence, a molecule designed to identify the important binding regions that a drug candidate compound would interact with. Using their drug discovery process, Salvino and the team identified a novel series of Mpro inhibitors with greater selectivity -- that is, more reliable at producing an inhibitory effect -- than the existing Mpro inhibitor for COVID-19 on the market.

The group's novel compounds successfully inhibited viral replication in vitro against three different COVID variants, including within lung tissue. The compound also synergized (i.e., achieved greater-than-the-sum-of-its-parts strength) with other existing antivirals in fighting the virus. In the preclinical testing, no apparent toxicities were observed -- a positive indication of the compound's safety.

"We're very excited to have identified such a promising new pathway for developing future therapies," said Salvino. "As we continue to refine the chemistry through further testing and optimization, we look forward to achieving improved potency in anti-coronaviral therapies."

Co-authors: Adi N. R. Poli, Ian Tietjen, Nitesh K. Nandwana, Joel Cassel, Troy E. Messick, Emery T. Register, Frederick Keeney, Luis J. Montaner, and Joseph M. Salvino of The Wistar Institute; and Rajesh Rajaiah, Atul K. Verma, Kabita Pandey, Arpan Acharya, and Siddappa N. Byrareddy of The University of Nebraska Medical Center.

Work supported by: NIH grants S10OD030245 and P30CA010815; Canadian Institutes of Health Research grant CIHR PJT-153057; and Commonwealth of Pennsylvania Special Initiatives Grant -- COVID-19 Funding, SAP #4100089371