Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.
Related Articles Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.
Biochem Pharmacol. 2020 11;181:114082
Authors: McMahon KL, Tay B, Deuis JR, Tanaka BS, Peigneur S, Jin AH, Tytgat J, Waxman SG, Dib-Hajj SD, Vetter I, Schroeder CI
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.
PMID: 32524995 [PubMed - indexed for MEDLINE]
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