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Publication Abstract from PubMed

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.

Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.,McMahon KL, Tay B, Deuis JR, Tanaka BS, Peigneur S, Jin AH, Tytgat J, Waxman SG, Dib-Hajj SD, Vetter I, Schroeder CI Biochem Pharmacol. 2020 Jun 7:114082. doi: 10.1016/j.bcp.2020.114082. PMID:32524995^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.