tetano
Editor, Senior Moderator
Sci Rep
. 2025 Feb 15;15(1):5671.
doi: 10.1038/s41598-025-89717-3. 9-aminominocycline potentiates the efficacy of EIDD-1931 and PF-332 by targeting the papain like protease enzyme of SARS-CoV-2
Kabita Pandey[SUP] #[/SUP][SUP] 1 [/SUP], Devin Shane M Lewis[SUP] #[/SUP][SUP] 2 [/SUP], Kyeongin Heo[SUP] 2 [/SUP], Arpan Acharya[SUP] 1 [/SUP], Travis Fields[SUP] 2 [/SUP], Kritika Gowda[SUP] 2 3 [/SUP], George Dean[SUP] 2 [/SUP], Srujana Rayalam[SUP] 2 [/SUP], Siddappa N Byrareddy[SUP] 4 [/SUP], Vicky Mody[SUP] 5 [/SUP], Shashidharamurthy Taval[SUP] 6 [/SUP]
Affiliations
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 IC[SUB]50[/SUB] 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 EC[SUB]50[/SUB] 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.
. 2025 Feb 15;15(1):5671.
doi: 10.1038/s41598-025-89717-3. 9-aminominocycline potentiates the efficacy of EIDD-1931 and PF-332 by targeting the papain like protease enzyme of SARS-CoV-2
Kabita Pandey[SUP] #[/SUP][SUP] 1 [/SUP], Devin Shane M Lewis[SUP] #[/SUP][SUP] 2 [/SUP], Kyeongin Heo[SUP] 2 [/SUP], Arpan Acharya[SUP] 1 [/SUP], Travis Fields[SUP] 2 [/SUP], Kritika Gowda[SUP] 2 3 [/SUP], George Dean[SUP] 2 [/SUP], Srujana Rayalam[SUP] 2 [/SUP], Siddappa N Byrareddy[SUP] 4 [/SUP], Vicky Mody[SUP] 5 [/SUP], Shashidharamurthy Taval[SUP] 6 [/SUP]
Affiliations
- PMID: 39955340
- PMCID: PMC11830066
- DOI: 10.1038/s41598-025-89717-3
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 IC[SUB]50[/SUB] 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 EC[SUB]50[/SUB] 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.