Selective Penicillamine Substitution Enables Development of a Potent Analgesic Peptide that Acts through a Non-Opioid-Based Mechanism

• Published in: Journal of medicinal chemistry Vol. 64; no. 13; pp. 9271 - 9278
• Main Authors: Gajewiak, Joanna, Christensen, Sean B, Dowell, Cheryl, Hararah, Fuaad, Fisher, Fernando, Huynh, Peter N, Olivera, Baldomero M, McIntosh, J. Michael
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-07-2021
• Subjects: Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Conotoxins - chemical synthesis; Conotoxins - chemistry; Conotoxins - pharmacology; Dose-Response Relationship, Drug; Drug Development; Humans; Molecular Structure; Neuralgia - drug therapy; Neuralgia - metabolism; Nicotinic Antagonists - chemical synthesis; Nicotinic Antagonists - chemistry; Nicotinic Antagonists - pharmacology; Receptors, Nicotinic - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00512

Venom-derived compounds are of broad interest in neuropharmacology and drug development. α-Conotoxins are small disulfide-containing peptides from Conus snails that target nicotinic acetylcholine receptors (nAChRs) and are in clinical development for non-opioid-based treatment of intractable pain. Although refined by evolution for interaction with target prey receptors, enhancements of pharmacological properties are needed for use in mammalian systems. Therefore, we synthesized analogues of α-conotoxin RgIA using a combination of selective penicillamine substitutions together with natural and non-natural amino acid replacements. This approach resulted in a peptide with 9000-fold increased potency on the human α9α10 nAChR and improved resistance to disulfide shuffling compared to the native peptide. The lead analogue, RgIA-5474, potently blocked α9α10 nAChRs, but not opioid- or other pain-related targets. In addition, RgIA-5474 effectively reversed chemotherapy-induced neuropathic pain.