Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.

Abstract

The role of voltage-gated sodium (NaV) channels in pain perception is indisputable. Of particular interest as targets for the development of pain therapeutics are the tetrodotoxin-resistant isoforms NaV1.8 and NaV1.9, based on animal as well as human genetic studies linking these ion channel subtypes to the pathogenesis of pain. However, only a limited number of inhibitors selectively targeting these channels have been reported. HSTX-I is a peptide toxin identified from saliva of the leech Haemadipsa sylvestris. The native 23-residue peptide, stabilised by two disulfide bonds, has been reported to inhibit rat NaV1.8 and mouse NaV1.9 with low micromolar activity, and may therefore represent a scaffold for development of novel modulators with activity at human tetrodotoxin-resistant NaV isoforms. We synthetically produced this hydrophobic peptide in high yield using a one-pot oxidation and single step purification and determined the three-dimensional solution structure of HSTX-I using NMR solution spectroscopy. However, in our hands, the synthetic HSTX-I displayed only very modest activity at human NaV1.8 and NaV1.9, and lacked analgesic efficacy in a murine model of inflammatory pain.

• Authors: Kirsten L McMahon, Bryan Tay, Jennifer R Deuis, Brian S Tanaka, Steve Peigneur, Ai-Hua Jin, Jan Tytgat, Stephen G Waxman, Sulayman D Dib-Hajj, Irina Vetter, Christina I Schroeder
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 181 Pg. 114082 (11 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32524995 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Analgesics
• Peptides
• Sodium Channel Blockers
• Solutions
• Toxins, Biological
• Voltage-Gated Sodium Channels

Topics

• Amino Acid Sequence
• Analgesics (chemistry, pharmacology)
• Animals
• Cells, Cultured
• Humans
• Hyperalgesia (prevention & control)
• Leeches (chemistry, metabolism)
• Magnetic Resonance Spectroscopy (methods)
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (cytology, drug effects, physiology)
• Patch-Clamp Techniques
• Peptides (chemistry, pharmacology)
• Rats, Sprague-Dawley
• Sodium Channel Blockers (chemistry, pharmacology)
• Solutions (chemistry)
• Toxins, Biological (chemistry, pharmacology)
• Voltage-Gated Sodium Channels (genetics, metabolism)