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Novel synthetic inhibitor of Ku/DNA interaction helps to reveal the mechanism of Ku-mediated regulation of HIV-1 transcriptionтезисы доклада Тезисы
- Авторы: Korolev Sergey, Pavlova E., Shadrina O., Mantsyzov A., Gottikh M.
- Сборник: Proceedings of 2nd Advanced Chemistry World Congress
- Тезисы
- Год издания: 2021
- Место издания: Peers Alley Media Vancouver BC, Canada
- Первая страница: 66
- Последняя страница: 66
- Аннотация: Human Ku protein participates in DNAdouble strand break repair and bindsto free ends of DNA. Besides Ku cancontribute to the transcription regulation ofcellular and viral genes through interaction withproteins and DNA, including transcription of oneog the most dangerous viruses – HIV-1 (humanimmunodeficiency virus). We investigated theeffect of Ku intracellular concentrations on thetranscription of the Firefly luciferase reporterprotein gene under the control of the LTR HIV-1 promoter in a pGL3 vector. It was found thatKu is a positive transcription factor from theHIV-1 LTR promoter. We decided to use Ku/DNA interaction inhibitors to elucidate whethersuch an effect can be determined by the directinteraction of the Ku protein with the HIV-1promoter. Using the available crystallographicstructure of Ku/DNA complex we built apharmacophore model describing key contactsof a DNA duplex with Ku and selected a seriesof the molecules fitting the pharmacophorevia virtual docking. We carried out EMSAexperimental screening on recombinant Kuand identified a new structural class of Ku/DNA interaction inhibitors with an IC50 withinmicromolar range. We showed that one of thecompounds effectively blocked the repair ofdouble-stranded DNA breaks in Hek 293T cells.However this compound was unable to influenceon the transcription of HIV-1 LTR promoter. Inthis regard we consider that Ku regulates HIV-1 transcription in DNA independent way. Thusthe series of new inhibitors of the interactionof Ku with DNA was discovered, which opensup prospects for further optimization of theirstructure in order to create even more activesubstances that can be used in the treatmentof cancer, as well as gene therapy. The workwas supported by Russian Science Foundationgrant RSF 17-14-01107-P.
- Добавил в систему: Готтих Марина Борисовна
Прикрепленные файлы
| № | Имя | Описание | Имя файла | Размер | Добавлен |
|---|---|---|---|---|---|
| 1. | Advanced_Chemistry_2021_Book_Final_1_66.pdf | Advanced_Chemistry_2021_Book_Final_1_66.pdf | 808,8 КБ | 24 ноября 2021 [gottikh] |