2. Academic Validation
  3. Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia

Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia

  • Mol Ther. 2025 Feb 5;33(2):771-785. doi: 10.1016/j.ymthe.2024.12.036.
Peter Oparin 1,  Oksana Khokhlova 2,  Aleksandr Cherkashin 3,  Kirill Nadezhdin 2,  Victor Palikov 2,  Yulia Palikova 2,  Yuliya Korolkova 2,  Irina Mosharova 2,  Olga Rogachevskaja 3,  Mikhail Baranov 2,  Ksenia Shaidullova 4,  Elizaveta Ermakova 4,  Vladislav Lushpa 2,  Alexandra Bruter 5,  Alexey Deykin 6,  Elena Ivanova 7,  Yulia Silaeva 5,  Igor Dyachenko 2,  Eduard Bocharov 8,  Guzel Sitdikova 4,  Alexander Andreev-Andrievskiy 9,  Dmitry Poteryaev 10,  Alexander Shuster 10,  Arkady Murashev 2,  Stanislav Kolesnikov 3,  Vasiliy Stepanenko 2,  Eugene Grishin 1,  Alexander Vassilevski 11
Affiliations

Affiliations

  • 1 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; Future Analgesics Ltd, Moscow 123060, Russia.
  • 2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.
  • 3 Institute of Cell Biophysics, Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino 142290, Moscow Region, Russia.
  • 4 Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420012, Russia.
  • 5 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia.
  • 6 Joint Center for Genetic Technology, Belgorod State University, Belgorod 308015, Russia.
  • 7 Zakusov Institute of Pharmacology, Moscow 125315, Russia.
  • 8 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; Moscow Institute of Physics and Technology (National Research University), Dolgoprudny 141701, Moscow Region, Russia.
  • 9 M.V. Lomonosov Moscow State University, Moscow 119991, Russia; Institute for Biomedical Problems, Russian Academy of Sciences, Moscow 123007, Russia.
  • 10 Future Analgesics Ltd, Moscow 123060, Russia.
  • 11 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; Future Analgesics Ltd, Moscow 123060, Russia; Moscow Institute of Physics and Technology (National Research University), Dolgoprudny 141701, Moscow Region, Russia. Electronic address: avas@ibch.ru.
PMID: 39960544 DOI: 10.1016/j.ymthe.2024.12.036
Abstract

P2X3 receptors are a validated molecular target in pain syndromes and chronic cough. Known P2X3 inhibitors generally suffer from poor selectivity and efficacy. Taking advantage of peptide combinatorial libraries found in venoms, we describe a P2X3 antagonist from the crab spider Thomisus onustus. This peptide potently inhibits P2X3 in the dorsal root and trigeminal ganglia neurons of rodents, as well as recombinant human P2X3, showing no effect on P2X2 or P2X2/3 receptors. PT6 presents a compact and rigid structure and produces pronounced antinociception in animal models of inflammatory and neuropathic pain at low doses (0.01-0.1 mg/kg subcutaneously). It does not show antinociceptive activity in P2rx3-knockout mice, providing further evidence in favor of its specificity. Importantly, PT6 shows no dysgeusia or ageusia effects, notoriously characteristic of small-molecule P2X3 ligands, and therefore stands out as an attractive hit for analgesic drug discovery.

Keywords

P2X receptor; migraine; neuropathy; neurotoxin; osteoarthritis; pain; peptide; purotoxin; toxin.

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