DNA sequence-specific ligands. XVIII. Synthesis, physico-chemical properties; genetic, virological, and biochemical studies of fluorescent dimeric bisbenzimidazoles DBPA(n)

Bioorg Med Chem. 2020 Apr 1;28(7):115378. doi: 10.1016/j.bmc.2020.115378.

Vasiliy S Koval ¹, Albert F Arutyunyan ¹, Victor I Salyanov ¹, Alexey A Kostyukov ², Olga E Melkina ³, Gennadii B Zavilgelsky ³, Regina R Klimova ⁴, Alla A Kushch ⁴, Sergey P Korolev ⁵, Yulia Yu Agapkina ⁵, Marina B Gottikh ⁵, Andrey V Vaiman ⁶, Ekaterina Yu Rybalkina ⁶, Olga Yu Susova ⁶, Alexei L Zhuze ⁷

Affiliations

1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
2 Emanuel Institute of Biochemical Physics, RAS, Moscow 119334, Russia.
3 Scientific Center "Kurchatov Institute", Research Institute of Genetics & Selection of Industrial Microorganisms, Moscow 117545, Russia.
4 Ivanovsky Institute of Virology, Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia.
5 Department of Chemistry and Belozersky Institute of Physicochemical Biology, Moscow State University, Moscow 119991, Russia.
6 Institute of Carcinogenesis, FSBI "N.N. Blokhin National Medical Research Center of Oncology", The Ministry of Health of the Russian Federation, 115478 Moscow, Russia.
7 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia. Electronic address: zhuze@eimb.ru.

PMID: 32089391 DOI: 10.1016/j.bmc.2020.115378

Abstract

A set of AT-specific fluorescent dimeric bisbenzimidazoles DBPA(n) with linkers of different lengths bound to DNA in the minor groove were synthesized and their genetic, virological, and biochemical studies were performed. The DBPA(n) were shown to be effective inhibitors of the histon-like protein H-NS, a regulator of the DNA transcription factor, as well as of the Aliivibrio logei Quorum Sensing regulatory system in E. coli cells. Their Antiviral activity was tested in model cell lines infected with herpes simplex virus type I. Also, it was found that DBPA(n) could inhibit catalytic activities of HIV-1 integrase at low micromolar concentrations. All of the dimeric bisbenzimidazoles DBPA(n) manifested fluorescent properties, were well soluble in water, nontoxic up to concentrations of 200 µM, and could penetrate into nuclei followed by binding to DNA.

Keywords

DNA; Fluorescent dimeric bisbenzimidazoles; HIV-1 integrase; HSV-1; Protein H-NS; Sequence-specific ligands.

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