2. Academic Validation
  3. Structure-guided design of broad-spectrum inhibitors of coronaviral proteases embodying a 1,3,2-oxazaphospholidin-3-one scaffold as a versatile design element

Structure-guided design of broad-spectrum inhibitors of coronaviral proteases embodying a 1,3,2-oxazaphospholidin-3-one scaffold as a versatile design element

  • Eur J Med Chem. 2026 May 26:316:119002. doi: 10.1016/j.ejmech.2026.119002.
Harry Nhat Nguyen 1,  Pulini S Ranasinghe 1,  I Kankanamge Ravindu S Ilesinghe 1,  Chamandi S Dampalla 1,  Athri D Rathnayake 1,  Zoie Liska 1,  Abdul-Rahman M Jesri 1,  Zeeshan Azmi 1,  Dustin E Nevonen 1,  Yunjeong Kim 2,  Adron R Ung 3,  Kyle E Taylor 3,  Anne Cooper 3,  Lijun Liu 3,  Kevin P Battaile 4,  Hayden A Thurman 1,  Egor Gusachenko 1,  Scott Lovell 5,  William C Groutas 6,  Kyeong-Ok Chang 7
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Wichita State University, Wichita, KS, 67260, USA.
  • 2 Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA.
  • 3 Protein Structure and X-ray Crystallography Laboratory, The University of Kansas, Lawrence, KS, 66047, USA.
  • 4 NYX, New York Structural Biology Center, Upton, NY, 11973, USA.
  • 5 Protein Structure and X-ray Crystallography Laboratory, The University of Kansas, Lawrence, KS, 66047, USA. Electronic address: [email protected].
  • 6 Department of Chemistry and Biochemistry, Wichita State University, Wichita, KS, 67260, USA. Electronic address: [email protected].
  • 7 Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA. Electronic address: [email protected].
PMID: 42208369 DOI: 10.1016/j.ejmech.2026.119002
Abstract

Constant changes in SARS-CoV-2 in human populations as well as potential future spillovers from animal coronaviruses have provided the impetus for the development of additional direct-acting antivirals. We describe herein the discovery of a new class of broad-spectrum inhibitors of coronavirus 3C-like protease (3CLpro), a cysteine protease essential for viral replication and a validated drug target, that incorporate in their structure a 1,3,2-oxazaphospholidin-3-one scaffold. Inhibitors 1 and 2 potently inhibited SARS-CoV-2 3CLpro (IC50 = 0.34 and 0.23 μM) and MERS-CoV 3CLpro (IC50 = 0.12 and 0.09 μM), and displayed Antiviral activity against SARS-CoV-2 (EC50 = 60 and 50 nM) with low cytotoxicity (CC50 > 100 μM). Importantly, several of the synthesized compounds inhibited recombinant human Cathepsin L with IC50 values in the low nM to sub-nM range. Thus, the compounds can potentially exhibit high Antiviral potency by abrogating viral entry via the inhibition of Cathepsin L and viral replication by inhibition of 3CLpro. High resolution cocrystal structures were determined to elucidate the mechanism of action, identify the molecular determinants associated with binding, and to inform the optimization process.

Keywords

1,3,2-oxazaphospholidin-3-one; Coronaviral protease inhibitors; MERS-CoV; SARS-CoV-2; Structure-guided design.

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