2. Academic Validation
  3. Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors

Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors

  • J Med Chem. 2024 Jun 13;67(11):9587-9598. doi: 10.1021/acs.jmedchem.4c00735.
Arik J Hone 1 2,  Ulises Santiago 3,  Peta J Harvey 4,  Bassel Tekarli 1,  Joanna Gajewiak 1,  David J Craik 4,  Carlos J Camacho 3,  J Michael McIntosh 1 5 6
Affiliations

Affiliations

  • 1 School of Biological Sciences, University of Utah, Salt Lake City, Utah 84112, United States.
  • 2 MIRECC, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah 84148, United States.
  • 3 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States.
  • 4 Institute for Molecular Bioscience, ARC Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 5 Department of Psychiatry, University of Utah, Salt Lake City, Utah 84112, United States.
  • 6 George E. Whalen Veterans Affairs Medical Center, Salt Lake City, Utah 84148, United States.
PMID: 38814877 DOI: 10.1021/acs.jmedchem.4c00735
Abstract

The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (682RRARS686) that forms a cleavage site for the enzyme Furin. Strikingly, the structure of the spike-protein loop containing the Furin cleavage site bears substantial similarity to neurotoxin peptides found in the venoms of certain snakes and marine cone snails. Leveraging this relationship, we designed and synthesized disulfide-constrained peptides with amino-acid sequences corresponding to the Furin cleavage-sites of wild-type (B.1 variant) SARS-CoV-2 or the Alpha, Delta, and Omicron variants. Remarkably, some of these peptides potently inhibited α7 and α9α10 nicotinic acetylcholine receptors (nAChR) with nM affinity and showed SARS-CoV-2 variant and nAChR subtype-dependent potencies. Nuclear magnetic resonance spectroscopy and molecular dynamics were used to rationalize structure-activity relationships between peptides and their cognate receptors. These findings delineate nAChR subtypes that can serve as high-affinity spike-protein targets in tissues central to COVID-19 pathophysiology and identify ligands and target receptors to inform the development of novel SARS-CoV-2 therapeutics.

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