Novel compounds show promise in combating COVID-19

New research from the Wistar Institute’s Salvino lab -; under the direction of Professor Joseph Salvino, Ph.D. -; has identified a novel series of SARS-CoV-2 Mpro inhibitors that may lead to potential new COVID-19 treatments that, based on preclinical testing, effectively inhibit COVID-19 and act synergistically with existing anti-COVID therapies. Their new discovery is detailed in the article “Design of Novel and Highly Selective SARS-CoV-2 Main Protease Inhibitors” published in the journal Antimicrobial agents and chemotherapy.

Despite effective vaccines approved for use worldwide, COVID-19 continues to contribute to mortality and morbidity -; a problem exacerbated by problems with access to vaccines and treatments. However, existing drug designs used for COVID-19 therapy pose a risk of drug interactions and a risk of incomplete virus inhibition.

To address this issue, Salvino -; a medicinal chemist at Wistar –; led a drug discovery team with the goal of improving the existing Mpro inhibitor design, an approach to viral therapy intended to prevent both viral replication and mutation-based drug resistance by targeting a component of the virus that regulates its ability to spread. And since Mpro is not an easily mutated biological trait like a spike protein, inhibiting Mpro can help maintain antiviral effectiveness even between different variations.

The team used a drug discovery technique that involved an “electrophilic acyloxymethyl ketone warhead.” Essentially, it is a molecule designed to identify the important binding regions with which a drug candidate would interact. Using their drug development process, Salvino and the team identified a novel series of Mpro inhibitors with greater selectivity -; that is, it produces an inhibitory effect more reliably -; than the existing Mpro inhibitor for COVID-19 on the market.

The group’s new compounds successfully inhibited virus replication in vitro against three different COVID variants, including in lung tissue. The compound also acted synergistically (i.e., achieved greater potency than the sum of its parts) with other existing antivirals in combating the virus. No apparent toxicities were observed in preclinical testing -; a positive sign of the security of the connection.

We are very pleased to have identified such a promising new avenue for the development of future therapies.”

Joseph Salvino, Professor, The Wistar Institute

“As we continue to refine the chemistry through further testing and optimization, we look forward to achieving improved efficacy in anti-coronaviral therapies.”