2. Academic Validation
  3. Discovery of the SARS-CoV-2 Papain-Like Protease Inhibitor MR1-114: From Structure-Based Design to In Vivo Antiviral Efficacy

Discovery of the SARS-CoV-2 Papain-Like Protease Inhibitor MR1-114: From Structure-Based Design to In Vivo Antiviral Efficacy

  • J Med Chem. 2026 Apr 9;69(7):8433-8450. doi: 10.1021/acs.jmedchem.5c03846.
Malla Reddy Gannarapu 1,  Divakar Indukuri 1,  Cameron Holberg 1,  Kiira Ratia 2,  Omar Lozano Ramos 1,  Savio Cardoza 1,  Ganga Reddy Velma 1,  Soumya Reddy Musku 1,  Zuohuang Qi 1,  Steve Slilaty 3,  Zuomei Li 3,  Lijun Rong 4,  Gregory R J Thatcher 1 5,  Rui Xiong 1
Affiliations

Affiliations

  • 1 Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, Arizona 85721, United States.
  • 2 Research Resources Center, University of Illinois Chicago (UIC), Chicago, Illinois 60612, United States.
  • 3 Sunshine Biopharma Inc., 333 Las Olas Way, CU4 Suite 433, Fort Lauderdale, Florida 33301, United States.
  • 4 Department of Microbiology, College of Medicine, University of Illinois (UIC), Chicago, Illinois 60612, United States.
  • 5 Department of Chemistry & Biochemistry, Colleges of Science and Medicine, University of Arizona, Tucson, Arizona 85721, United States.
PMID: 41886743 DOI: 10.1021/acs.jmedchem.5c03846
Abstract

The SARS-CoV-2 papain-like protease (PLpro) is a critical target for Antiviral intervention. Here, we report the discovery of MR1-114 (compound 15), a potent, noncovalent PLpro inhibitor. Guided by structure-based design, we incorporated a strategic alkyne linker hypothesized to access the cryptic Val70Ub pocket, a modification that proved critical for driving cellular potency. Multiparameter optimization yielded MR1-114, which displays a desirable ADME profile characterized by high solubility, permeability, and hepatocyte stability, translating to high oral bioavailability in mice and rats. Notably, the compound exhibits preferential lung enrichment in mice and rats while maintaining broad-spectrum activity against variants, including Delta and Omicron BA.5 with nanomolar potency in vitro. In the K18-hACE2 mouse model, oral administration of MR1-114 matched the therapeutic efficacy of nirmatrelvir, significantly suppressing pulmonary viral replication and preventing disease-associated weight loss.

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