SARS-CoV-2 Papain-Like Protease (PLpro) Inhibitors

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Invention Summary:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a global health risk despite the availability of vaccines and two oral antivirals, molnupiravir and Paxlovid. Limitations including modest efficacy, drug–drug interactions, and the emergence of resistance, particularly to nirmatrelvir, highlight the urgent need for additional oral antivirals with novel mechanisms of action. The papain-like protease (PLpro) is an essential viral enzyme required for polyprotein processing and viral replication, and also suppresses host innate immune responses through deubiquitinating and deISGylating activities. No FDA-approved PLpro inhibitors currently exist, positioning PLpro as a high-value and differentiated antiviral target.

Rutgers researchers have developed a broad and integrated portfolio of structure-guided small-molecule PLpro inhibitors that collectively advance therapeutic innovation, resistance robustness, and oral antiviral development.

• Potent small-molecule PLpro inhibitors: engage novel binding pockets, exhibiting nanomolar IC₅₀ values, strong antiviral activity, favorable pharmacokinetics, and oral bioavailability. 
• Quinoline-derived PLpro inhibitors: Lead compound Jun13296 demonstrated robust in vivo antiviral efficacy, supporting clinical development potential, including activity against drug-resistant strains.

• Fumaramide-based PLpro inhibitors: Compounds such as Jun13728 exhibit potent inhibition across multiple SARS-CoV-2 variants, including nirmatrelvir-resistant mutants, with supportive in vitro and in vivo PK data.
• PLpro-targeting PROTACs: A novel antiviral strategy inducing selective degradation of PLpro via the ubiquitin–proteasome system, offering prolonged viral suppression, restoration of innate immune signaling, and a higher genetic barrier to resistance.

Market Applications:

PLpro inhibitors represent a differentiated antiviral class suitable:

• For stand-alone therapy or combination regimens with existing COVID-19 antivirals.
• Pandemic preparedness.
• SARS-CoV-2 variants, including nirmatrelvir-resistant strains.

Advantages:

•  First-in-class, structure-guided mechanism of action by high-resolution X-ray crystal structures
•  Dual antiviral mechanism: Inhibits viral replication while restoring host innate immune signaling
•  Broad variant and resistance coverage:
•  Orally tractable, drug-like small molecules with validated in vivo efficacy

Publications:

• 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; PMCID: PMC11825904.

Intellectual Property & Development Status: Patents pending. Available for licensing and/or research collaboration. For any business development and other collaborative partnerships, contact:  marketingbd@research.rutgers.edu