麻豆传媒

News — PHILADELPHIA — (October 8, 2024) — New research from The Wistar Institute’s Salvino lab — led by professor , Ph.D. — has identified a novel series of SARS-CoV-2 Mpro inhibitors that may lead to potential new COVID-19 treatments that, according to preclinical testing, effectively inhibits COVID-19 and synergizes with existing anti-COVID therapies. Their new discovery is detailed in the paper, “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 — 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

Publication information: “Design of novel and highly selective SARS-CoV-2 main protease inhibitors,” from

ABOUT THE WISTAR INSTITUTE

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. .