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Новосибирский институт органической химии им. Н.Н. Ворожцова
Сибирского отделения Российской академии наук

На сайте  журнала Viruses   (IF=5,048) опубликована статья  с участием сотрудников Института: д.х.н. О.И. Яровой (внс, ЛФАВ), к.х.н. А.С. Соколовой (снс ЛФАВ), Е.Д. Мордвиновой (лаборант ЛФАВ), к.х.н. А.Д. Рогачева (снс ЛФАВ)  и чл.-корр. РАН, д.х.н., проф. Н.Ф. Салахутдинова (зав. отделом медицинской химии)


Borneol Ester Derivatives as Entry Inhibitors of a Wide Spectrum of SARS-CoV-2 Viruses

Olga I. Yarovaya, Dmitriy N. Shcherbakov, Sophia S. Borisevich, Anastasiya S. Sokolova, Maxim A. Gureev, Edward M. Khamitov, Nadezda B. Rudometova, Anastasiya V. Zybkina, Ekaterina D. Mordvinova, Anna V. Zaykovskaya, Artem D. Rogachev, Oleg V. Pyankov, Rinat A. Maksyutov and Nariman F. Salakhutdinov

Viruses 202214(6), 1295
Publication Date: Jun 14, 2022


 https://doi.org/10.3390/v14061295

(This article belongs to the Special Issue SARS-CoV-2 and Other Coronaviruses)


Abstract

In the present work we studied the antiviral activity of the home library of monoterpenoid derivatives using the pseudoviral systems of our development, which have glycoproteins of the SARS-CoV-2 virus strains Wuhan and Delta on their surface. We found that borneol derivatives with a tertiary nitrogen atom can exhibit activity at the early stages of viral replication. In order to search for potential binding sites of ligands with glycoprotein, we carried out additional biological tests to study the inhibition of the re-receptor-binding domain of protein S. For the compounds that showed activity on the pseudoviral system, a study using three strains of the infectious SARS-CoV-2 virus was carried out. As a result, two leader compounds were found that showed activity on the Wuhan, Delta, and Omicron strains. Based on the biological results, we searched for the potential binding site of the leader compounds using molecular dynamics and molecular docking methods. We suggested that the compounds can bind in conserved regions of the central helices and/or heptad repeats of glycoprotein S of SARS-CoV-2 viruses. View Full-TextIt is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.


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