Dual-Action Tetrapeptide Analogue of Psychrophilic Fungal Origin: Potent Inhibitor of Human Nicotinic Acetylcholine Receptors with Antinociceptive and Muscle-Relaxant Activity

  • J Med Chem. 2025 Dec 25;68(24):26175-26187. doi: 10.1021/acs.jmedchem.5c02238.
Lu Lu  1  2 ,  Han-Shen Tae  3 ,  Cheng Ge  1  2 ,  Xuekai Zhang  4 ,  Teng Pan  1  2 ,  Zixuan Zhang  1  2 ,  Tao Jiang  1  2 ,  Wenqing Cai  5 ,  David J Adams  3 ,  Rilei Yu  1  2
Affiliations
  • 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
  • 2. Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
  • 3. Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • 4. Department of Biological Engineering, College of Chemical and Biological Engineering, Shandong University of Science and Technology, Qingdao 266590, China.
  • 5. Shandong Academy of Pharmaceutical Sciences, 989 Xinluo St., Jinan 250101, China.
PMID: 41331772 DOI: 10.1021/acs.jmedchem.5c02238
Abstract

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating synaptic transmission at neuromuscular junctions and within both the central and peripheral nervous systems. The psychrophilic Fungal tetrapeptide WvVf-OCH3 exhibits ∼55% inhibition of human muscle-type nAChR (hα1β1εδ) at 10 μM, suggesting potential for optimization. Structure-activity studies identified analogues, WrFr-OCH3 and WrFk-OCH3, with significantly increased potency (75-90% inhibition at 1 μM) against hα1β1εδ nAChRs and, notably, the hα9α10 subtype. These analogues exhibit high-affinity binding through stable π-π stacking with the principal face and electrostatic interactions with the complementary face of the receptor binding site. Their unique alternating L/D chirality enhances proteolytic stability. In vivo, intravenous application of WrFr-OCH3 alleviated oxaliplatin-induced cold allodynia, while intramuscular injection reduced forelimb grip strength, consistent with muscle relaxant activity. Together, these findings identify WrFr-OCH3 as the shortest high-activity peptide ligand of human nAChRs reported to date, with therapeutic potential for both inflammatory pain management and muscle relaxation.

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