Triterpenic Acid Amides as Potential Inhibitors of the SARS-CoV-2 Main Protease

Baev, Dmitry S.; Blokhin, Mikhail; Chirkova, V. Yu.; Belenkaya, S. V.; Luzina, O. A.; Yarovaya, Оlga I.; Салахутдинов, Н. Ф.; Щербаков, Д. Н.

doi:10.3390/molecules28010303

Cited by 6 publications

(2 citation statements)

References 34 publications

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“…The results obtained are consistent with the results published earlier (Jin et al, 2020), (Lockbaum et al, 2021;Zakharova et al, 2021) (Figure 4), which confirms that 3SL retains its properties when expressed in E. coli cells. The use of this test system makes it possible both to detect new inhibitors of the main viral protease (Baev et al, 2022) and to study the mechanism of action of compounds that have shown activity against the infectious SARS-CoV-2 virus (Filimonov et al, 2022).…”

Section: Authenticity Analysis Of the 3cl Proteasementioning

confidence: 99%

The main protease 3CLpro of the SARS-CoV-2 virus: how to turn an enemy into a helper

Belenkaya

Merkuleva

Yarovaya

et al. 2023

Front. Bioeng. Biotechnol.

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Despite the long history of use and the knowledge of the genetics and biochemistry of E. coli, problems are still possible in obtaining a soluble form of recombinant proteins in this system. Although, soluble protein can be obtained both in the cytoplasm and in the periplasm of the bacterial cell. The latter is a priority strategy for obtaining soluble proteins. The fusion protein technology followed by detachment of the fusion protein with proteases is used to transfer the target protein into the periplasmic space of E. coli. We have continued for the first time to use the main viral protease 3CL of the SARS-CoV-2 virus for this purpose. We obtained a recombinant 3CL protease and studied its complex catalytic properties. The authenticity of the resulting recombinant enzyme, were confirmed by specific activity analysis and activity suppression by the known low-molecular-weight inhibitors. The catalytic efficiency of 3CL (0.17 ± 0.02 µM-1-s-1) was shown to be one order of magnitude higher than that of the widely used tobacco etch virus protease (0.013 ± 0.003 µM-1-s-1). The application of the 3CL gene in genetically engineered constructs provided efficient specific proteolysis of fusion proteins, which we demonstrated using the receptor-binding domain of SARS-CoV-2 spike protein and GST fusion protein. The solubility and immunochemical properties of RBD were preserved. It is very important that in work we have shown that 3CL protease works effectively directly in E. coli cells when co-expressed with the target fusion protein, as well as when expressed as part of a chimeric protein containing the target protein, fusion partner, and 3CL itself. The results obtained in the work allow expanding the repertoire of specific proteases for researchers and biotechnologists.

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Section: Authenticity Analysis Of the 3cl Proteasementioning

confidence: 99%

The main protease 3CLpro of the SARS-CoV-2 virus: how to turn an enemy into a helper

Belenkaya

Merkuleva

Yarovaya

et al. 2023

Front. Bioeng. Biotechnol.

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“…One of the encouraging fields of medicinal chemistry for the synthesis of new agents with antiviral activity is the use of natural compounds as a starting platform, which has recently received special attention [ 17 , 18 , 19 , 20 ]. We have earlier identified effective borneol-based inhibitors of entry of a wide range of SARS-CoV-2 viruses using a pseudoviral system [ 21 ], using a surrogate system of triterpene acid–based amides as inhibitors of the main viral protease [ 22 ]. Glycyrrhizic acid nicotinates have also been shown to be inhibitors of SARS-CoV-2 viruses [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses

Yarovaya,

Filimonov,

Baev

et al. 2024

Viruses

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Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, (+)-3e demonstrated pronounced antiviral activity against all the strains.

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Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS‐CoV‐2 main protease

de Carvalho,

Souza,

Tizziani

et al. 2024

Archiv der Pharmazie

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The present work reports the inhibitory effect of amides derived from gallic acid (gallamides) against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease (Mpro), along with cytotoxicity evaluation and molecular docking studies. In addition to gallamides, other relevant compounds were also synthesized and evaluated against Mpro, making a total of 25 compounds. Eight compounds presented solubility issues during the inhibitory assay and one showed no inhibitory activity. Compounds 3a, 3b, and 3f showed the highest enzymatic inhibition with IC50 = 0.26 ± 0.19 µM, 0.80 ± 0.38 µM, and 2.87 ± 1.17 µM, respectively. Selenogallamide 6a exhibited IC50 values of 5.42 ± 2.89 µM and a comparison with its nonselenylated congener 3c shows that the insertion of the chalcogen moiety improved the inhibitory capacity of the compound by approximately 10 times. Regarding the cellular toxicity in THP‐1 and Vero cells, compounds 3e and 3g, showed moderate cytotoxicity in Vero cells, while for THP‐1 both were nontoxic, with CC50 > 150 µM. Derivative 3d showed moderate cytotoxicity against both cell lines, whereas 6d was moderatly toxic to THP‐1. Other compounds analyzed do not induce substantial cellular toxicity at the concentrations tested. The molecular docking results for compounds 3a, 3b, and 3f show that hydrogen bonding interactions involving the hydroxyl groups (OH) of the gallate moiety are relevant, as well as the carbonyl group.

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Triterpenic Acid Amides as Potential Inhibitors of the SARS-CoV-2 Main Protease

Cited by 6 publications

References 34 publications

The main protease 3CLpro of the SARS-CoV-2 virus: how to turn an enemy into a helper

The main protease 3CLpro of the SARS-CoV-2 virus: how to turn an enemy into a helper

The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses

Synthesis, in vitro and in silico evaluation of gallamide and selenogallamide derivatives as inhibitors of the SARS‐CoV‐2 main protease

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