Natural Guanine Derivatives Exert PARP-Inhibitory and Cytoprotective Effects in a Model of Cardiomyocyte Damage under Oxidative Stress

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Stanislav I. Shram^1,a*, Tatyana A. Shcherbakova², Tatyana V. Abramova³, Erzhena C. Baradieva¹, Anna S. Efremova⁴, Maria S. Smirnovskaya⁵, Vladimir N. Silnikov³, Vytas K. Švedas^2,6, and Dmitry K. Nilov^2,b*

¹Institute of Molecular Genetics, National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia

²Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, 119991 Moscow, Russia

³Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences, Siberian Branch, 630090 Novosibirsk, Russia

⁴Research Centre for Medical Genetics, 115522 Moscow, Russia

⁵Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia

⁶Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

^* To whom correspondence should be addressed.

Received December 13, 2022; Revised March 27, 2023; Accepted March 27, 2023

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Inhibitors of human poly(ADP-ribose) polymerase (PARP) are considered as promising agents for treatment of cardiovascular, neurological, and other diseases accompanied by inflammation and oxidative stress. Previously, the ability of natural compounds 7-methylguanine (7mGua) and 8-hydroxy-7-methylguanine (8h7mGua) to suppress activity of the recombinant PARP protein was demonstrated. In the present work, we have investigated the possibility of PARP-inhibitory and cytoprotective action of 7mGua and 8h7mGua against the rat cardiomyoblast cultures (undifferentiated and differentiated H9c2). It was found that 7mGua and 8h7mGua rapidly penetrate into the cells and effectively suppress the H₂O₂-stimulated PARP activation (IC₅₀ = 270 and 55 μM, respectively). The pronounced cytoprotective effects of 7mGua and 8h7mGua were shown in a cellular model of oxidative stress, and effectiveness of 8h7mGua exceeded the classic PARP inhibitor 3-aminobenzamide. The obtained data indicate promise for the development of PARP inhibitors based on guanine derivatives and their testing using the models of ischemia–reperfusion tissue damage.

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KEY WORDS: 7-methylguanine, 8-hydroxy-7-methylguanine, poly(ADP-ribose) polymerase, inhibitor, cardiomyocytes, oxidative stress, cytoprotection

DOI: 10.1134/S0006297923060068

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