Pharmacological activity and NMR solution structure of the leech peptide HSTX-I.
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.
['McMahon|Kirsten L|KL|', 'Tay|Bryan|B|', 'Deuis|Jennifer R|JR|', 'Tanaka|Brian S|BS|', 'Peigneur|Steve|S|', 'Jin|Ai-Hua|AH|', 'Tytgat|Jan|J|', 'Waxman|Stephen G|SG|', 'Dib-Hajj|Sulayman D|SD|', 'Vetter|Irina|I|', 'Schroeder|Christina I|CI|']
D000595:Amino Acid Sequence D000700:Analgesics D000818:Animals D002478:Cells, Cultured D006801:Humans D006930:Hyperalgesia D007865:Leeches D009682:Magnetic Resonance Spectroscopy D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009474:Neurons D018408:Patch-Clamp Techniques D010455:Peptides D017207:Rats, Sprague-Dawley D026941:Sodium Channel Blockers D012996:Solutions D014118:Toxins, Biological D061566:Voltage-Gated Sodium Channels
NMR Leech Chronic pain Electrophysiology Voltage-gated sodium channels