Related Experiment Video

Updated: Jul 12, 2026

Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
05:50

Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro

Published on: September 26, 2025

Aromatic π-stacking stabilizes an α-helical SARS-CoV-2 MPER peptide that mimics the post-fusion spike and enables

Michael Quagliata1, Sonja Bazhenova2, Rosaria Arvia3

  • 1Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Via Della Lastruccia 13, Sesto Fiorentino, I-50019, Italy.

European Journal of Medicinal Chemistry
|July 10, 2026
PubMed

Insights

Short peptides derived from the SARS-CoV-2 spike protein’s membrane-proximal external region (MPER) show potent antiviral activity. Aromatic interactions stabilize these peptides, offering a new strategy for developing SARS-CoV-2 entry inhibitors.

Area of Science:

  • Biochemistry
  • Virology
  • Structural Biology

Background:

  • SARS-CoV-2 entry into host cells relies on spike protein-mediated membrane fusion.
  • The membrane-proximal external region (MPER) of the spike protein is crucial for viral entry.
  • MPER contains a tryptophan-rich sequence implicated in fusion.

Purpose of the Study:

  • To explore MPER-derived peptides as potential antiviral agents against SARS-CoV-2.
  • To investigate the structural basis of MPER peptide antiviral activity.
  • To understand the role of aromatic residues and secondary structure in peptide efficacy.

Main Methods:

  • Synthesis and antiviral evaluation of truncated MPER peptides against SARS-CoV-2 variants.
  • Time-dependent antiviral assays to assess peptide efficacy post-infection.
  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine peptide structure in solution and membrane-mimetic environments.

Main Results:

  • MPER peptides demonstrated potent antiviral activity with nanomolar IC50 values, particularly those rich in aromatic residues.
  • Antiviral activity was time-dependent, diminishing when peptides were added 1 hour post-infection.
  • NMR revealed stable alpha-helical conformations stabilized by intramolecular aromatic π-π stacking interactions (Trp, Tyr).

Conclusions:

  • Aromatic stacking stabilizes MPER peptide alpha-helicity, mimicking post-fusion spike structure.
  • This structural mechanism correlates with enhanced antiviral potency.
  • Findings provide insights for designing peptide-based SARS-CoV-2 entry inhibitors.

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