2. Academic Validation
  3. Structure-activity relationship and nsp15-dependent mechanism of spirothiazolidinone derivatives with pan-coronavirus activity

Structure-activity relationship and nsp15-dependent mechanism of spirothiazolidinone derivatives with pan-coronavirus activity

  • Bioorg Chem. 2026 Sep 5:179:109995. doi: 10.1016/j.bioorg.2026.109995.
Benjamin Van Loy 1,  Çağla Begüm Apaydın 2,  Sam Noppen 3,  Julie Vandeput 4,  Arnout Voet 5,  Gökçe Cihan-Üstündağ 6,  Lieve Naesens 7,  Annelies Stevaert 8
Affiliations

Affiliations

  • 1 Rega Institute, Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Fatih, 34452, Istanbul, Turkey. Electronic address: [email protected].
  • 3 Rega Institute, Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].
  • 4 Rega Institute, Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 5 Laboratory of Biomolecular Modelling and Design, Department of Chemistry, KU Leuven, Celestijnenlaan 200G, 3001 Heverlee, Belgium. Electronic address: [email protected].
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Fatih, 34452, Istanbul, Turkey. Electronic address: [email protected].
  • 7 Rega Institute, Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].
  • 8 Rega Institute, Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected].
PMID: 42160828 DOI: 10.1016/j.bioorg.2026.109995
Abstract

The ubiquitous presence of pathogenic coronaviruses (CoVs) in humans and Animals underscores the need for small-molecule antivirals with pan-CoV efficacy. Here, we report the design and synthesis of a novel series of spirothiazolidinone derivatives (2a-2p), prepared via an efficient one-pot cyclocondensation reaction. The compounds were initially evaluated for Antiviral activity against human CoVs HCoV-229E and SARS-CoV-2. Analysis of the structure-activity relationship revealed that Antiviral potency and selectivity were strongly influenced by the substituent at C-8 of the spirocyclic core, with bulky hydrophobic or aromatic groups yielding the most favourable profiles. The resulting lead compound, 2p, was evaluated against a broader panel of human and animal CoVs, including HCoV-NL63, HCoV-OC43, murine hepatitis virus (MHV-A59) and porcine transmissible gastroenteritis virus (TGEV). 2p demonstrated pan-CoV activity, with EC90 values ranging from 2.2 to 30 μM, and without cytotoxicity at 100 μM. Virus selected for 2p resistance carried mutations in nsp15, a CoV non-structural protein with endoribonuclease (EndoU) functionality. Biochemical EndoU assays showed no inhibition by 2p, while surface plasmon resonance demonstrated direct binding to nsp15, indicating non-catalytic target engagement. Time-of-compound-addition experiments showed that 2p exerts its inhibitory effect during the post-entry phase of the CoV life cycle. 2p displayed additive Antiviral effect when combined with the CoV polymerase inhibitor GS-441524, indicating mechanistic complementarity and potential for combination therapy. Collectively, these findings position our spirothiazolidinones as promising leads for further optimization toward pan-CoV drug development.

Keywords

Spirothiazolidinone; antiviral; inhibitor; nsp15; pan-coronavirus activity.

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