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

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.