Presenting Author: Shashidharamurthy Taval
, Associate Professor at Philadelphia Col. of Osteopathic Med., South Georgia
Abstract:
The 3CLpro, PLpro, and RdRp are vital for SARS-CoV-2 replication, targeted by drugs like Paxlovid® and Lagevrio™ for COVID-19. However, PLpro lacks specific drug targeting, which is crucial for viral replication and immune response. This study identified 9-Aminominocyclin (9-AMN) as a SARS-CoV-2 PLpro inhibitor. While minocycline alone did not hinder these enzymes, introducing an amino group at the 9th carbon position led to over 90% inhibition of PLpro's proteolytic and DUB functions (IC50: 4.15µM and 4.55µM). Structural analysis revealed 9-AMN's binding to PLpro's catalytic site, disrupting its activities. 9-AMN did not harm uninfected lung cells (up to 50µM) but reduced SARS-CoV-2 infection by 70% at 6.25µM, causing only 25-35% cytotoxicity in infected cells. It inhibited Delta and Omicron variants (IC50: 1.04µM and 2.35µM). Combining 9-AMN with EIDD-1931 and Nirmatrelvir showed synergistic effects, significantly reducing doses required for similar potency against SARS-CoV-2 Omicron infection. Overall, 9-AMN is a potent SARS-CoV-2 replication inhibitor, preserving the host's immune response by suppressing PLpro's DUB activity. However, before potential clinical trials, further preclinical studies are needed for therapeutic viability and safety.
9-amino minocycline potentiated the anti-SARS-CoV-2 effects of EIDD-1931 and PF-322 by selectively targeting papain-like protease (PLpro) enzyme