Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease

  • J Med Chem. 2026 Feb 12;69(3):3588-3608. doi: 10.1021/acs.jmedchem.5c03704.
Qiangqiang Wei  1 ,  Ashley J Taylor  1 ,  Nagaraju Miriyala  1 ,  Mahesh A Barmade  1 ,  Zachary O Gentry  1 ,  Jordan Anderson-Daniels  2 ,  Kevin B Teuscher  1 ,  Mackenzie M Crow  1 ,  Chideraa Apakama  1 ,  Taylor M South  1 ,  Tyson A Rietz  1 ,  Kangsa Amporndanai  1 ,  Jason Phan  1 ,  John L Sensintaffar  1 ,  Mark Denison  2 ,  Taekyu Lee  1 ,  Stephen W Fesik  1  3  4
Affiliations
  • 1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.
  • 2. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 3. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600, United States.
  • 4. Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
PMID: 41629155 DOI: 10.1021/acs.jmedchem.5c03704
Abstract

The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new Antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PLPro led to the identification of a novel class of spiro[chromane-2,4'-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and Antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.

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