9BAF

Solution NMR structure of conofurin-Delta

Summary for 9BAF

• Entry DOI: 10.2210/pdb9baf/pdb
• NMR Information: BMRB: 31156
• Descriptor: Alpha-conotoxin LvIA (1 entity in total)
• Functional Keywords: conotoxin, nicotinic acetylcholine receptor, neuropeptide
• Biological source: Conus lividus
• Total number of polymer chains: 1
• Total formula weight: 1753.07

Authors

Harvey, P.J.,Craik, D.J.,Hone, A.J.,McIntosh, J.M. (deposition date: 2024-04-04, release date: 2024-07-03, Last modification date: 2024-10-16)

Primary citation

Hone, A.J.,Santiago, U.,Harvey, P.J.,Tekarli, B.,Gajewiak, J.,Craik, D.J.,Camacho, C.J.,McIntosh, J.M.
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., 67:9587-9598, 2024

PubMed Abstract: The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (RRARS) 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.

PubMed: 38814877
DOI: 10.1021/acs.jmedchem.4c00735

Experimental method

SOLUTION NMR