Selective Inhibition of <i>Enterovirus A</i> Species Members’ Reproduction by Furano[2, 3‐<i>d</i>]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

Kozlovskaya, Liubov I.; Golinets, Anastasia D.; Eletskaya, Anastasia A.; Orlov, Alexey A.; Palyulin, Vladimir A.; Kochetkov, Sergey N.; Alexandrova, L. A.; Osolodkin, Dmitry I.

doi:10.1002/slct.201703052

Cited by 24 publications

(14 citation statements)

References 32 publications

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“…EV cytopathic effect inhibition test: Cytopathic effect inhibition test against representatives of Enterovirus genus was performed as described previously 12 . Eight 2-fold dilutions of stock solutions of the HS samples (concentration of 1 µg/mL) were prepared in 2×EMEM medium to obtain a final concentration series starting from 50 μg/mL.…”

Section: Methodsmentioning

confidence: 99%

Examination of molecular space and feasible structures of bioactive components of humic substances by FTICR MS data mining in ChEMBL database

Orlov

Zherebker

Eletskaya

et al. 2019

Sci Rep

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Humic substances (HS) are complex natural mixtures comprising a large variety of compounds produced during decomposition of decaying biomass. The molecular composition of HS is extremely diverse as it was demonstrated with the use of high resolution mass spectrometry. The building blocks of HS are mostly represented by plant-derived biomolecules (lignins, lipids, tannins, carbohydrates, etc.). As a result, HS show a wide spectrum of biological activity. Despite that, HS remain a ‘biological activity black-box’ due to unknown structures of constituents responsible for the interaction with molecular targets. In this study, we investigated the antiviral activity of eight HS fractions isolated from peat and coal, as well as of two synthetic humic-like materials. We determined molecular compositions of the corresponding samples using ultra-high resolution Fourier-transform ion cyclotron resonance mass-spectrometry (FTICR MS). Inhibitory activity of HS was studied with respect to reproduction of tick-borne encephalitis virus (TBEV), which is a representative of Flavivirus genus, and to a panel of enteroviruses (EVs). The samples of natural HS inhibited TBEV reproduction already at a concentration of 1 µg/mL, but they did not inhibit reproduction of EVs. We found that the total relative intensity of FTICR MS formulae within elemental composition range commonly attributed to flavonoid-like structures is correlating with the activity of the samples. In order to surmise on possible active structural components of HS, we mined formulae within FTICR MS assignments in the ChEMBL database. Out of 6502 formulae within FTICR MS assignments, 3852 were found in ChEMBL. There were more than 71 thousand compounds related to these formulae in ChEMBL. To support chemical relevance of these compounds to natural HS we applied the previously developed approach of selective isotopic exchange coupled to FTICR MS to obtain structural information on the individual components of HS. This enabled to propose compounds from ChEMBL, which corroborated the labeling data. The obtained results provide the first insight onto the possible structures, which comprise antiviral components of HS and, respectively, can be used for further disclosure of antiviral activity mechanism of HS.

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Section: Methodsmentioning

confidence: 99%

Examination of molecular space and feasible structures of bioactive components of humic substances by FTICR MS data mining in ChEMBL database

Orlov

Zherebker

Eletskaya

et al. 2019

Sci Rep

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“…1 Certain small molecule TBEV inhibitors were recently suggested and tested against Eu strains Neudoerfl and Hypr 10,11 or Absettarov. [12][13][14] We reported several series of potent TBEV reproduction inhibitors 15,16 identified with the help of molecular docking against the n-octyl-b-D-glucoside (b-OG) binding pocket 17 in the homology model of TBEV envelope protein ectodomain sE, which plays a pivotal role in the process of pH-driven membrane fusion between viral particles and host cell vesicles during endocytosis and viral entry. 18 Among them, 4-aminopyrimidine Noxides have shown a good efficiency against strain Absettarov coupled with a low cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Spectrum of antiviral activity of 4-aminopyrimidine N-oxides against a broad panel of tick-borne encephalitis virus strains

Dueva

Tuchynskaya

Kozlovskaya

et al. 2020

Antivir Chem Chemother

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Tick-borne encephalitis is an important human arbovirus neuroinfection spread across the Northern Eurasia. Inhibitors of tick-borne encephalitis virus (TBEV) strain Absettarov, presumably targeting E protein n-octyl-β-d-glucoside (β-OG) pocket, were reported earlier. In this work, these inhibitors were tested in vitro against seven strains representing three main TBEV subtypes. The most potent compound, 2-[(2-methyl-1-oxido-5,6,7,8-tetrahydroquinazolin-4-yl)amino]-phenol, showed EC50 values lower than 22 µM against all the tested strains. Nevertheless, EC50 values for virus samples of certain strains demonstrated a substantial variation, which appeared to be consistent with the presence of E protein not only in infectious virions, but also in non-infectious and immature virus particles, protein aggregates, and membrane complexes.

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“…Cytopathic effect (CPE) inhibition test against representatives of Enterovirus genus was performed as described previously …”

Section: Methodsmentioning

confidence: 99%

Getting to Know the Neighbours with GTM: The Case of Antiviral Compounds

Orlov

Khvatov

Koruchekov

et al. 2019

Molecular Informatics

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Recent outbreaks of dangerous viral infections, such as Ebola virus disease, Zika fever, etc., are forcing the search for new antiviral compounds. Preferably, such compounds should possess broad‐spectrum antiviral activity, as the development of drugs for the treatment of dozens of viral infections lacking specific treatment would require significant resources. Antiviral activity data present in public resources are very sparse and further investigation of structure‐activity relationships is necessary. One of the strategies could be the investigation of chemical space around known active compounds and assessment of activity against closely related viruses in order to fill in the antiviral activity matrix. Here we present an investigation of antiviral activity using universal maps built with generative topographic mapping (GTM) algorithm. The GTM‐based maps were used to find commercially available compounds in close proximity to already known compounds with anti‐flaviviral and anti‐enteroviral activities. Selected compounds were then assessed in cell‐based assays against tick‐borne encephalitis virus (TBEV) and a panel of enteroviruses. This approach allowed us to identify 23 new compounds showing anti‐TBEV activity with EC50 values in micromolar and submicromolar range.

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Selective Inhibition of Enterovirus A Species Members’ Reproduction by Furano[2, 3‐d]pyrimidine Nucleosides Revealed by Antiviral Activity Profiling against (+)ssRNA Viruses

Cited by 24 publications

References 32 publications

Examination of molecular space and feasible structures of bioactive components of humic substances by FTICR MS data mining in ChEMBL database

Examination of molecular space and feasible structures of bioactive components of humic substances by FTICR MS data mining in ChEMBL database

Spectrum of antiviral activity of 4-aminopyrimidine N-oxides against a broad panel of tick-borne encephalitis virus strains

Getting to Know the Neighbours with GTM: The Case of Antiviral Compounds

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