Publication:
Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors

Файлы
W2971650850.pdf(917.57 KB)
Дата
2019
Авторы
Lebedev, DmitryS.
Kryukova, ElenaV.
Ivanov, IgorA.
Egorova, NataliaS.
Tsetlin, VictorI.
Journal Title
Journal ISSN
Volume Title
Издатель
Научные группы
Организационные подразделения
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Организационная единица
Инженерно-физический институт биомедицины
Цель ИФИБ и стратегия развития – это подготовка высококвалифицированных кадров на базе передовых исследований и разработок новых перспективных методов и материалов в области инженерно-физической биомедицины. Занятие лидерских позиций в биомедицинских технологиях XXI века и внедрение их в образовательный процесс, что отвечает решению практикоориентированной задачи мирового уровня – диагностике и терапии на клеточном уровне социально-значимых заболеваний человека.
Выпуск журнала
Аннотация
Many peptide ligands of nicotinic acetylcholine receptors (nAChRs) contain a large number of positively charged amino acid residues, a striking example being conotoxins RgIA and GeXIVA from marine mollusk venom, with an arginine content of >30%. To determine whether peptides built exclusively from arginine residues will interact with different nAChR subtypes or with their structural homologs such as the acetylcholine-binding protein and ligand-binding domain of the nAChR alpha 9 subunit, we synthesized a series of R3, R6, R8, and R16 oligoarginines and investigated their activity by competition with radioiodinated a-bungarotoxin, two-electrode voltage-clamp electrophysiology, and calcium imaging. R6 and longer peptides inhibited muscle-type nAChRs, alpha 7 nAChRs, and alpha 3 beta 2 nAChRs in the micromolar range. The most efficient inhibition of ion currents was detected for muscle nAChR by R16 (IC50 = 157 nM) and for the alpha 9 alpha 10 subtype by R8 and R16 (IC50 = 44 and 120 nM, respectively). Since the R8 affinity for other tested nAChRs was 100-fold lower, R8 appears to be a selective antagonist of alpha 9 alpha 10 nAChR. For R8, the electrophysiological and competition experiments indicated the existence of two distinct binding sites on alpha 9 alpha 10 nAChR. Since modified oligoarginines and other cationic molecules are widely used as cell-penetrating peptides, we studied several cationic polymers and demonstrated their nAChR inhibitory activity. SIGNIFICANT STATEMENT By using radioligand analysis, electrophysiology, and calcium imaging, we found that oligoarginine peptides are a new group of inhibitors for muscle nicotinic acetylcholine receptors (nAChRs) and some neuronal nAChRs, the most active being those with 16 and 8 Arg residues. Such compounds and other cationic polymers are cell-penetrating tools for drug delivery, and we also demonstrated the inhibition of nAChRs for several of the latter. Possible positive and negative consequences of such an action should be taken into account.
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Цитирование
Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors / Lebedev, DmitryS [et al.] // Molecular Pharmacology. - 2019. - 96. - № 5. - P. 664-673;. - 10.1124/mol.119.117713
URI
https://www.doi.org/10.1124/mol.119.117713
 https://www.scopus.com/record/display.uri?eid=2-s2.0-85073183368&origin=resultslist
 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS_CPL&DestLinkType=FullRecord&UT=WOS:000490862800015
 https://openrepository.mephi.ru/handle/123456789/19695
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