Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65160910.31857/S0869813923010041IYEAZZEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИStructural Optimization of an α-Hairpinin Blocking Potassium Channels KV1.3Оптимизация структуры α-гарпинина, блокирующего калиевые каналы KV1.3GigolaevA. M.ГиголаевА. М.avas@ibch.ruTabakmakherV. M.ТабакмахерВ. М.avas@ibch.ruPeigneurS.ПеньёрС.avas@ibch.ruTytgatJ.ТитгатЯ.avas@ibch.ruVassilevskiA. A.ВасилевскийА. А.avas@ibch.ruShemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesИнститут биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова Российской академии наукKU LeuvenЛёвенский университетMoscow Institute of Physics and Technology (State University)Московский физико-технический институт (государственный университет)01012023109110911801022025Copyright ©; 2023, А.М. Гиголаев, В.М. Табакмахер, С. Пеньёр, Я. Титгат, А.А. ВасилевскийCopyright ©; 2023, А.М. Гиголаев, В.М. Табакмахер, С. Пеньёр, Я. Титгат, А.А. Василевский2023А.М. Гиголаев, В.М. Табакмахер, С. Пеньёр, Я. Титгат, А.А. ВасилевскийА.М. Гиголаев, В.М. Табакмахер, С. Пеньёр, Я. Титгат, А.А. Василевскийhttps://journals.eco-vector.com/0869-8139/article/view/651609

Obtaining compounds with specificity for certain isoforms of ion channels is a significant problem of curent physiology and pharmacology. In a series of papers, we have shown that the α-hairpinin fold can serve as a template for the rational design of peptide ligands of potassium channels. Here, we used molecular modeling to optimize the structure of the previously obtained Tk-hefu-10 peptide, a selective KV1.3 channel blocker, with a half-maximal inhibitory concentration (IC50) of ≈150 nM. Molecular dynamics simulation of the Tk-hefu-10–KV1.3 complex provided information on the interaction of individual amino acid residues of the peptide and channel, and the analysis of these interactions made it possible to propose amino acid substitutions in the structure of Tk-hefu-10 to increase its affinity. Novel Tk-hefu-12 peptide is a truncated analog of Tk-hefu-10 by one residue with five substitutions; it is characterized by an IC50 value of ≈70 nM against KV1.3. In addition, there are no methionine residues in the structure of Tk-hefu-12, which makes it possible to obtain Tk-hefu peptides using cyanogen bromide.

Актуальной задачей современной физиологии и фармакологии является получение соединений, обладающих специфичностью в отношении определенных изоформ ионных каналов. В серии статей мы показали, что α-гарпининовая укладка может служить шаблоном для рационального проектирования пептидных лигандов калиевых каналов. В данной работе было использовано молекулярное моделирование, чтобы оптимизировать структуру ранее полученного пептида Tk-hefu-10, селективного блокатора каналов KV1.3, полумаксимальная концентрация ингибирования (ИК50) для которого составляет ≈150 нМ. Расчеты молекулярной динамики комплекса Tk-hefu-10–KV1.3 предоставили информацию о взаимодействии отдельных аминокислотных остатков пептида и канала, а анализ этих взаимодействий позволил предложить аминокислотные замены в структуре Tk-hefu-10 для увеличения его аффинности. Новый пептид Tk-hefu-12 представляет собой укороченный на один остаток аналог Tk-hefu-10 с пятью заменами; экспериментальная проверка активности показала, что его ИК50 ≈ 70 нМ против KV1.3. Кроме того, в структуре Tk-hefu-12 отсутствуют остатки метионина, что позволяет перейти к получению пептидов линейки Tk-hefu с использованием бромциана.

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