2. Academic Validation
  3. 9-aminominocycline potentiates the efficacy of EIDD-1931 and PF-332 by targeting the papain like protease enzyme of SARS-CoV-2

9-aminominocycline potentiates the efficacy of EIDD-1931 and PF-332 by targeting the papain like protease enzyme of SARS-CoV-2

  • Sci Rep. 2025 Feb 15;15(1):5671. doi: 10.1038/s41598-025-89717-3.
Kabita Pandey # 1,  Devin Shane M Lewis # 2,  Kyeongin Heo 2,  Arpan Acharya 1,  Travis Fields 2,  Kritika Gowda 2 3,  George Dean 2,  Srujana Rayalam 2,  Siddappa N Byrareddy 4,  Vicky Mody 5,  Shashidharamurthy Taval 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Centre, Omaha, NE, 68198, USA.
  • 2 Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Suwanee, GA, 30024, USA.
  • 3 The Johns Hopkins University, Baltimore, MD, 21218, USA.
  • 4 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Centre, Omaha, NE, 68198, USA. sid.byrareddy@unmc.edu.
  • 5 Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Suwanee, GA, 30024, USA. vickymo@pcom.edu.
  • 6 Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Suwanee, GA, 30024, USA. rangaiahsh@pcom.edu.
  • # Contributed equally.
PMID: 39955340 DOI: 10.1038/s41598-025-89717-3
Abstract

The 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp) are key Enzymes in SARS-CoV-2 replication and serve as critical targets for an Antiviral drug. Currently, Paxlovid® and Lagevrio™ specifically target 3CLpro and RdRp, respectively, for COVID-19 treatment. However, no antivirals target for the SARS-CoV-2 Plpro enzyme, essential for viral replication and suppression of the host Antiviral immune response. This study identified 9-aminominocycline (9-AMN) as a potent inhibitor of SARS-CoV-2 Plpro. Unlike the parent compound minocycline, 9-AMN inhibits PLpro's proteolytic and Deubiquitinase activities by approximately 90%, with IC50 values of 4.15 µM and 4.55 µM, respectively, while showing no effect on the enzymatic activity of 3CLpro or RdRp. Enzyme kinetics reveal that 9-AMN functions as a mixed PLpro inhibitor and binds to its active site, disrupting its function as predicted by computer modeling. Furthermore, 9-AMN demonstrates, efficacy against the Delta and Omicron variants, with EC50 values of 1.04 µM and 2.35 µM, respectively. When combined with EIDD-1931 (an active form of molnupiravir) or nirmatrelvir (PF-332), 9-AMN exhibits synergistic effects, significantly reducing the doses required to inhibit the Omicron variant. In conclusion, 9-AMN inhibits SARS-CoV-2 replication, and PLpro activity, highlighting its potential as a promising candidate for COVID-19 treatment strategies.

Keywords

Enzyme kinetics; PLpro inhibitor; Replication; SARS-CoV-2.

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