Synthesis of plyphenol-containing cationic linear and dendrimeric peptides with anti-oxidant activity

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Abstract

Natural polyphenols are of great interest from the point of view of their use for the pharmacological control of oxidative stress and many diseases. However, the low bioavailability and rapid metabolism of polyphenols in the form of glycosides or aglycones stimulates the search for effective means of delivery into systemic circulation. Conjugation of polyphenols with cationic amphiphilic peptides can result in compounds with strong antioxidant activity and the ability to cross biological barriers. Such compounds may be in demand as drugs for antioxidant therapy, including for the treatment of viral, oncological and neurodegenerative diseases due to the diverse range of biological activities inherent in polyphenols and peptides. In this work, cationic linear and dendrimer amphiphilic cationic peptides were synthesized by the solid phase method, and a number of peptides were conjugated to gallic acid (Ga). Ga is a non-toxic natural phenolic acid and an important functional element of many flavonoids with high antioxidant activity. It was shown that the resulting Ga-peptide conjugates exhibited antioxidant (antiradical) activity that was 2-3 times higher than that of ascorbic acid. Other tests indicated that the addition of Ga did not affect the toxicity and hemolytic activity of the conjugates. Ga-modified peptides stimulated the transmembrane transfer of the pGL3 plasmid encoding the luciferase reporter gene; however, the addition of Ga to the N-terminus of the peptide reduced its transfection activity. Some of the resulting compounds had noticeable inhibitory activity against the E. сoli-Dh5α strain.

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About the authors

A. A. Shatilov

“NRC Institute of Immunology” FMBA of Russia

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow

S. M. Andreev

“NRC Institute of Immunology” FMBA of Russia

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow

A. V. Shatilova

“NRC Institute of Immunology” FMBA of Russia

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow

E. A. Turetskiy

“NRC Institute of Immunology” FMBA of Russia; Sechenov First Moscow State Medical University (Sechenov University)

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow; 119991 Moscow

R. A. Kurmasheva

“NRC Institute of Immunology” FMBA of Russia; Sechenov First Moscow State Medical University (Sechenov University)

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow; 119991 Moscow

M. O. Babikhina

“NRC Institute of Immunology” FMBA of Russia; MIREA – Russian Technological University

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow; 119454 Moscow

L. V. Saprigina

“NRC Institute of Immunology” FMBA of Russia; MIREA – Russian Technological University

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow; 119454 Moscow

N. N. Shershakova

“NRC Institute of Immunology” FMBA of Russia

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow

D. K. Bolyakina

“NRC Institute of Immunology” FMBA of Russia

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow

V. V. Smirnov

“NRC Institute of Immunology” FMBA of Russia; Sechenov First Moscow State Medical University (Sechenov University)

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow; 119991 Moscow

I. P. Shilovsky

“NRC Institute of Immunology” FMBA of Russia

Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow

M. R. Khaitov

“NRC Institute of Immunology” FMBA of Russia; Pirogov Russian National Research Medical University

Author for correspondence.
Email: sm.andreev@nrcii.ru
Russian Federation, 115522 Moscow; 117997 Moscow

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Supplementary files

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2. Fig. 1. Mass spectra (MALDI-TOF) of synthesized peptides: a – AB-9, b – AB-10, c – AB-11, d – AB-12, d – AB-13, e – AB-14, g – AB-15, h – ST-10, i – AB-32, j – AB-33, k – AST-1

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3. Fig. 2. Absorption spectra in the UV and visible regions: left – AB-33, right – AB-32.

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4. Fig. 3. Hemolytic activity of peptides, % of erythrocyte hemolysis in distilled water: 1 – AB-10, 2 – AB-11, 3 – AB-12, 4 – AB-13, 5 – AB-14, 6 – AB-15, 7 – ST-10, 8 – AST-1

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5. Fig. 4. Fluorescence level (538 nm) of the intracellular sensor HyPer in the presence of peptides, measured before and after addition of hydrogen peroxide. 1 – Positive control, 2 – AB-10, 3 – AB-11, 4 – AB-12, 5 – AB-13, 6 – AB-14, 7 – AB-15, 8 – AST-1, 9 – ST-10. Peptides marked with asterisks have fluorescence intensity after addition of hydrogen peroxide that differed statistically significantly (p < 0.05) from the positive control.

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6. Fig. 5. Comparative activity of peptides in stimulating transfection of the pGL3 plasmid encoding the luciferase reporter gene, expressed as mean values ​​± SE. 1 – Lipofectamine 3000, 2 – AB-10, 3 – AB-11, 4 – AB-12, 5 – AB-13, 6 – AB-14, 7 – AB-15, 8 – AB-32, 9 – AB-33, 10 – AST-1, 11 – ST-10, 12 – PBS (negative control)

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