Peptide-derived ligands for the discovery of safer opioid analgesics

• Published in: Drug discovery today 2024-05, Vol.29 (5), p.103950, Article 103950
• Main Authors: Eliasof, Abbe, Liu-Chen, Lee-Yuan, Li, Yangmei
• Format: Article
• Language: English
• ISSN: 1359-6446; 1878-5832; 1878-5832
• DOI: 10.1016/j.drudis.2024.103950

•Endogenous opioid peptides produce analgesia without side effects.•Opioid peptides produce different spatiotemporal activation patterns from small molecules.•Structural modification including cyclization, unnatural amino acid replacement, N-methylation, and glycosylation improve the bioavailability of peptide.•Peptide-based opioid ligands are promising candidates for the discovery and development of efficacious, safer, and non-/less addictive analgesics. Drugs targeting the μ-opioid receptor (MOR) remain the most efficacious analgesics for the treatment of pain, but activation of MOR with current opioid analgesics also produces harmful side effects, notably physical dependence, addiction, and respiratory depression. Opioid peptides have been accepted as promising candidates for the development of safer and more efficacious analgesics. To develop peptide-based opioid analgesics, strategies such as modification of endogenous opioid peptides, development of multifunctional opioid peptides, G protein-biased opioid peptides, and peripherally restricted opioid peptides have been reported. This review seeks to provide an overview of the opioid peptides that produce potent antinociception with much reduced side effects in animal models and highlight the potential advantages of peptides as safer opioid analgesics.