2. Academic Validation
  3. Discovery of a tetrahydrobenzothiophen-2-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide-based PROTAC as degrader of SARS-CoV-2 main protease

Discovery of a tetrahydrobenzothiophen-2-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide-based PROTAC as degrader of SARS-CoV-2 main protease

  • Eur J Med Chem. 2026 May 5:309:118721. doi: 10.1016/j.ejmech.2026.118721.
Michela Eleuteri 1,  Alessandro Bazzacco 2,  Beatrice Mercorelli 3,  Jenny Desantis 4,  Alessia Zago 2,  Gabriele Cruciani 1,  Arianna Loregian 5,  Laura Goracci 6
Affiliations

Affiliations

  • 1 DAISY Lab, Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy.
  • 2 Department of Molecular Medicine, University of Padua, Padua, Italy.
  • 3 Department of Molecular Medicine, University of Padua, Padua, Italy. Electronic address: beatrice.mercorelli@unipd.it.
  • 4 DAISY Lab, Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy. Electronic address: jenny.desantis@unipg.it.
  • 5 Department of Molecular Medicine, University of Padua, Padua, Italy; Microbiology and Virology Unit, Padua University Hospital, Padua, Italy.
  • 6 DAISY Lab, Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy. Electronic address: laura.goracci@unipg.it.
PMID: 41780340 DOI: 10.1016/j.ejmech.2026.118721
Abstract

Targeted protein degradation has emerged as a new strategy in drug development, particularly in the anti-cancer field. Although still limited, in recent years, the application of Proteolysis Targeting Chimera (PROTAC) technology against viral infections has been investigated, establishing its broad therapeutic potential. Here, we present the design, synthesis, and biological characterization of a series of PROTACs targeting SARS-CoV-2 Main Protease (MPro) based on a previously identified MPro inhibitor linked to ligands of either Von-Hippel Lindau (VHL) or Cereblon (CRBN) E3 Ligase. Among the synthesized compounds, the VHL-addressing PROTAC 6 emerged as the most potent Mpro degrader, effectively reducing SARS-CoV-2 Mpro protein levels in infected 293T-hACE2 cells with a DC50 value of 0.9 μM and a Dmax of almost 90% at 25 μM. In parallel, it displayed Antiviral activity against SARS-CoV-2 in the low micromolar range, also confirmed in the disease-relevant model of human lung Calu-3 cells, and retained activity against the human endemic coronavirus HCoV-OC43. PROTAC 6 resulted inactive in inhibiting SARS-CoV-2 Mpro catalytic activity in vitro and mechanistic studies confirmed that its Antiviral activity is due to the binding and successive induction of degradation of SARS-CoV-2 Mpro. Kinetic solubility experiments showed that PROTAC 6 exhibits very low solubility in phosphate-buffered saline solution but significant higher solubility in two biorelevant dissolution media mimicking intestinal conditions under fasted and fed states, as FaSSIF and FeSSIF. In conclusion, we developed SARS-CoV-2 Mpro degraders based on a novel warhead and confirmed the significant role of targeted protein degradation technology in advancing the identification of new, effective anti-coronavirus PROTACs.

Keywords

Antiviral; Main protease; Microscale thermophoresis; PROTACs; SARS-CoV-2; Targeted protein degradation.

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