2. Academic Validation
  3. Selective Penicillamine Substitution Enables Development of a Potent Analgesic Peptide that Acts through a Non-Opioid-Based Mechanism

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

  • J Med Chem. 2021 Jul 8;64(13):9271-9278. doi: 10.1021/acs.jmedchem.1c00512.
Joanna Gajewiak 1,  Sean B Christensen 1,  Cheryl Dowell 1,  Fuaad Hararah 1,  Fernando Fisher 1,  Peter N Huynh 1,  Baldomero M Olivera 1,  J Michael McIntosh 1 2 3
Affiliations

Affiliations

  • 1 School of Biological Sciences, University of Utah, 257 South 1400 East, Salt Lake City, Utah 84112-0840, United States.
  • 2 George E. Wahlen Department of Veterans Affairs Medical Center, 500 Foothill Dr., Salt Lake City, Utah 84148, United States.
  • 3 Department of Psychiatry, University of Utah, 501 Chipeta Way, Salt Lake City, Utah 84108, United States.
PMID: 34142837 DOI: 10.1021/acs.jmedchem.1c00512
Abstract

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.

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