Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia

Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia Научная публикация

Журнал

Molecular therapy
ISSN: 1525-0016 , E-ISSN: 1525-0024

Вых. Данные

Год: 2025, Том: 33, Номер: 2, Страницы: 771-785 Страниц : 15 DOI: 10.1016/j.ymthe.2024.12.036

Авторы

Oparin Peter ^1,2 , Khokhlova Oksana ¹ , Cherkashin Aleksandr ³ , Nadezhdin Kirill ¹ , Palikov Victor ¹ , Palikova Yulia ¹ , Korolkova Yuliya ¹ , Mosharova Irina ¹ , Rogachevskaja Olga ³ , Baranov Mikhail ¹ , Shaidullova Ksenia ⁴ , Ermakova Elizaveta ⁴ , Lushpa Vladislav ¹ , Bruter Alexandra ⁵ , Deykin Alexey ⁶ , Ivanova Elena ⁷ , Silaeva Yulia ⁵ , Dyachenko Igor ¹ , Bocharov Eduard ^1,8 , Sitdikova Guzel ⁴ , Andreev-Andrievskiy Alexander ^9,10 , Poteryaev Dmitry ² , Shuster Alexander ² , Murashev Arkady ¹ , Kolesnikov Stanislav ³ , Stepanenko Vasiliy ¹ , Grishin Eugene ^1,2 , Vassilevski Alexander ^1,2,8

Организации

1	Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
2	Future Analgesics Ltd, Moscow 123060, 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	Moscow Institute of Physics and Technology (National Research University), Dolgoprudny 141701, Moscow Region, Russia
9	M.V. Lomonosov Moscow State University, Moscow 119991, Russia
10	Institute for Biomedical Problems, Russian Academy of Sciences, Moscow 123007, Russia

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.

Oparin P. , Khokhlova O. , Cherkashin A. , Nadezhdin K. , Palikov V. , Palikova Y. , Korolkova Y. , Mosharova I. , Rogachevskaja O. , Baranov M. , Shaidullova K. , Ermakova E. , Lushpa V. , Bruter A. , Deykin A. , Ivanova E. , Silaeva Y. , Dyachenko I. , Bocharov E. , Sitdikova G. , Andreev-Andrievskiy A. , Poteryaev D. , Shuster A. , Murashev A. , Kolesnikov S. , Stepanenko V. , Grishin E. , Vassilevski A.
Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia
Molecular therapy. 2025. V.33. N2. P.771-785. DOI: 10.1016/j.ymthe.2024.12.036 OpenAlex

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