Synthesis and Biological Properties of Polyphenol-Containing Linear and Dendrimeric Cationic Peptides

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Artem A. Shatilov¹, Sergey M. Andreev^1,a*, Anastasiya V. Shatilova¹, Evgeny A. Turetskiy^1,2, Renata A. Kurmasheva^1,2, Marina O. Babikhina^1,3, Larisa V. Saprygina^1,3, Nadezhda N. Shershakova¹, Dar’ya K. Bolyakina¹, Valeriy V. Smirnov^1,2, Igor P. Shilovsky¹, and Musa R. Khaitov^1,4

¹“NRC Institute of Immunology” FMBA of Russia, 115522 Moscow, Russia

²Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia

³MIREA – Russian Technological University, 119454 Moscow, Russia

⁴Pirogov Russian National Research Medical University, 117997 Moscow, Russia

Received August 25, 2023; Revised December 4, 2023; Accepted December 8, 2023

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Natural polyphenols are promising compounds for the pharmacological control of oxidative stress in various diseases. However, low bioavailability and rapid metabolism of polyphenols in a form of glycosides or aglycones have stimulated the search for the vehicles that would provide their efficient delivery to the systemic circulation. Conjugation of polyphenols with cationic amphiphilic peptides yields compounds with a strong antioxidant activity and ability to pass through biological barriers. Due to a broad range of biological activities characteristic of polyphenols and peptides, their conjugates can be used in the antioxidant therapy, including the treatment of viral, oncological, and neurodegenerative diseases. In this work, we synthesized linear and dendrimeric cationic amphiphilic peptides that were then conjugated with gallic acid (GA). GA is a non-toxic natural phenolic acid and an important functional element of many flavonoids with a high antioxidant activity. The obtained GA-peptide conjugates showed the antioxidant (antiradical) activity that exceeded 2-3 times the antioxidant activity of ascorbic acid. GA attachment had no effect on the toxicity and hemolytic activity of the peptides. GA-modified peptides stimulated the transmembrane transfer of the pGL3 plasmid encoding luciferase reporter gene, although GA attachment at the N-terminus of peptides reduced their transfection activity. Several synthesized conjugates demonstrated the antibacterial activity in the model of Escherichia coli Dh5α growth inhibition.

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KEY WORDS: cationic peptides, dendrimers, gallic acid, anti-radical activity, hemolysis, cytotoxicity, ROS, HyPer, transfection

DOI: 10.1134/S0006297924010115

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