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

Author:

McMahon, Kirsten L

Tay, Bryan

Deuis, Jennifer R

Tanaka, Brian S

Peigneur, Steve

Jin, Ai-Hua

Tytgat, Jan

Waxman, Stephen G

Dib-Hajj, Sulayman D

Vetter, Irina

Schroeder,Christina
Author Address

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia., Center for Neuroscience and Regeneration Research, New Haven, CT, United States; Department of Neurology Yale University School of Medicine, New Haven, CT, United States; Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States., Toxicology and Pharmacology, Katholieke Universiteit (KU) Leuven, Campus Gasthuisberg, Leuven, Belgium., Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, 4103, Australia. Electronic address: i.vetter@imb.uq.edu.au., Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia; National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, United States. Electronic address: christina.schroeder@nih.gov.,

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. Copyright © 2020. Published by Elsevier Inc.

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