The quest for effective COVID-19 treatments has led to the development of broad-spectrum oral antivirals, focusing on conserved viral targets such as proteases. As the COVID-19 pandemic has accelerated antiviral and vaccine development, priorities have been given to conserved viral targets. This is especially important given the potential for drug resistance to current treatments. A collaboration between Jun Wang’s lab at the Rutgers Ernest Mario School of Pharmacy and Eddy Arnold’s lab at Rutgers Center for Advanced Biotechnology & Medicine addresses this need by presenting the design and evaluation of quinoline-containing SARS-CoV-2 papain-like protease (PLpro) inhibitors as potential oral antiviral drug candidates.
The researchers designed quinoline analogs targeting the Val70Ub site of PLpro, a viral enzyme involved in replication and immune evasion. X-ray crystal structures revealed that the designed compounds could bind to either the Val70Ub site or, in a flipped orientation, to the BL2 groove. One promising candidate, Jun13296, exhibited favorable drug properties and potent antiviral activity against SARS-CoV-2 variants, including those resistant to nirmatrelvir.
In a mouse model of SARS-CoV-2 infection, oral administration of Jun13296 led to improved survival rates, reduced weight loss, decreased viral load in the lungs, and prevention of lung tissue damage. These results suggest that quinoline PLpro inhibitors hold significant promise as oral antiviral treatments for SARS-CoV-2.
Several key findings contributed to this conclusion:
Rational Design: The researchers strategically designed quinoline-based inhibitors to interact with the Val70Ub site of PLpro, enhancing binding affinity.
Structural Insights: X-ray crystallography provided detailed information on how these inhibitors bind to PLpro, guiding further optimization.
Potent In Vitro Activity: Jun13296 demonstrated strong enzymatic inhibition and antiviral activity in cell-based assays. It was found to have a 10-fold improvement in antiviral activity compared to the control Jun12682.
Favorable Pharmacokinetics: Jun13296 exhibited acceptable oral bioavailability and maintained effective plasma concentrations in mice. The oral bioavailability of Jun13296 was found to be 32.8%.
Broad Spectrum Activity: Jun13296 was effective against both SARS-CoV-2 variants and nirmatrelvir-resistant strains.
In Vivo Efficacy: Jun13296 significantly improved outcomes in a mouse model of SARS-CoV-2 infection, reducing disease severity and mortality.
The development of Jun13296 and related quinoline-containing PLpro inhibitors represents a significant step forward in the search for effective COVID-19 treatments, particularly in the face of emerging drug resistance. While a similar compound (PF-07957472) has been reported by Pfizer, Jun13296 displayed more potent antiviral activity and a different binding orientation. Further research is warranted to fully elucidate the potential of PLpro inhibition as a therapeutic strategy and to optimize these inhibitors for clinical use.
Jadhav P, Liang X, Ansari A, Tan B, Tan H, Li K, Chi X, Ford A, Ruiz FX, Arnold E, Deng X, Wang J. Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates. Nat Commun. 2025 Feb 13;16(1):1604. doi: 10.1038/s41467-025-56902-x. PMID: 39948104. https://www.nature.com/articles/s41467-025-56902-x
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