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

Dueva, Evgenia V.; Tuchynskaya, Ksenia; Kozlovskaya, Liubov I.; Osolodkin, Dmitry I.; Sedenkova, Kseniya N.; Averina, Elena B.; Palyulin, Vladimir A.; Karganova, Galina G.

doi:10.1177/2040206620943462

Cited by 14 publications

(27 citation statements)

References 34 publications

(63 reference statements)

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“…The main direction of our research is emphasized by the fact that TBEV population is comprised of a wide variety of structurally different viral particles, which could affect both the development of the immune response during flavivirus infection [73] and the outcomes of the virus challenge studies. Moreover, the number of non-infectious viral particles in the studied TBEV strains exceeded the number of infectious viral particles 100 to 1000 times, as was shown before [47,74]. It is known for mosquito-borne flaviviruses that the number of non-infectious immature virus particles may depend on the reproduction system or individual characteristics of the strain [75].…”

Section: Discussionsupporting

confidence: 65%

“…Plaque assay was performed as described earlier [47] on PEK cell monolayers in 24-well plates. Serial 10-fold dilutions of TBEV were incubated with PEK cells for 1 h at 37 • C in a CO 2 -incubator, coated with 1.26% methylcellulose (Sigma, St Louis, MO, USA) in medium 199 with Hanks' and Earle's salts (2:1, v:v) and 2% FBS, and left for incubation for 6 days at 37 • C in a CO 2 -incubator.…”

Section: Plaque Assay and 50% Plaque Reduction Neutralization Test (Prnt 50 )mentioning

confidence: 99%

“…Brain samples of sacrificed mice were weighed and manually homogenized in medium 199 to obtain 10% suspensions, which were aliquoted and stored at −70 • C. Total RNA was isolated from the brain suspension according to the protocol described earlier [47]. A fixed amount (5.5 log RNA copies per sample) of attenuated type I Sabin poliovirus vaccine strain was added to each sample as an internal control [61,62].…”

Section: Sample Preparation and Rna Quantification (Qrt-pcr)mentioning

confidence: 99%

“…For the primers see Table S1. Quantitative RT-PCR (qRT-PCR) was performed according to a modified method described earlier [47,62] on Dyad Disciple thermal cycler with a Chromo4 detector (BioRad, Hercules, CA, USA), using Taq polymerase, RealTime PCR kit and primers (Synthol, Moscow, Russia). TBEV RNA levels were measured in duplicates and expressed as log of viral RNA equivalents per ml of the sample after comparison with a standard prepared as described in [63].…”

Section: Sample Preparation and Rna Quantification (Qrt-pcr)mentioning

confidence: 99%

“…An ensemble of particles is produced during flavivirus infection, including mature infectious virions, immature and partially mature virions, the envelope protein E aggregates [40][41][42][43][44], and dead-end noninfectious structures formed as a result of short-term exposure to increased temperatures [45]. Each of these structures carries the protein E on its surface in a variety of conformational positions, however, they are partially or completely non-infectious, and thus can interfere with the infectious virions in functional assays, affect the assessment of the effective concentration of antivirals targeting the protein E [46,47] or immune response.…”

Section: Introductionmentioning

confidence: 99%

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Experimental Assessment of Possible Factors Associated with Tick-Borne Encephalitis Vaccine Failure

et al. 2021

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Currently the only effective measure against tick-borne encephalitis (TBE) is vaccination. Despite the high efficacy of approved vaccines against TBE, rare cases of vaccine failures are well documented. Both host- and virus-related factors can account for such failures. In this work, we studied the influence of mouse strain and sex and the effects of cyclophosphamide-induced immunosuppression on the efficacy of an inactivated TBE vaccine. We also investigated how an increased proportion of non-infectious particles in the challenge TBE virus would affect the protectivity of the vaccine. The vaccine efficacy was assessed by mortality, morbidity, levels of viral RNA in the brain of surviving mice, and neutralizing antibody (NAb) titers against the vaccine strain and the challenge virus. Two-dose vaccination protected most animals against TBE symptoms and death, and protectivity depended on strain and sex of mice. Immunosuppression decreased the vaccine efficacy in a dose-dependent manner and changed the vaccine-induced NAb spectrum. The vaccination protected mice against TBE virus neuroinvasion and persistence. However, viral RNA was detected in the brain of some asymptomatic animals at 21 and 42 dpi. Challenge with TBE virus enriched with non-infectious particles led to lower NAb titers in vaccinated mice after the challenge but did not affect the protective efficacy.

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Section: Discussionsupporting

confidence: 65%

Section: Plaque Assay and 50% Plaque Reduction Neutralization Test (Prnt 50 )mentioning

confidence: 99%

Section: Sample Preparation and Rna Quantification (Qrt-pcr)mentioning

confidence: 99%

Section: Sample Preparation and Rna Quantification (Qrt-pcr)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Experimental Assessment of Possible Factors Associated with Tick-Borne Encephalitis Vaccine Failure

et al. 2021

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Tetrahydroquinazoline N‐oxide derivatives inhibit reproduction of tick‐borne and mosquito‐borne flaviviruses

Sedenkova

Uvarova

Назарова

et al. 2023

Archiv der Pharmazie

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Tick‐borne encephalitis virus (TBEV), yellow fever virus (YFV), and West Nile virus (WNV) are flaviviruses causing emerging arthropod‐borne infections of a great public health concern. Clinically approved drugs are not available to complement or replace the existing vaccines, which do not provide sufficient coverage. Thus, the discovery and characterization of new antiflaviviral chemotypes would advance studies in this field. In this study, a series of tetrahydroquinazoline N‐oxides was synthesized, and the antiviral activity of the compounds was assessed against TBEV, YFV, and WNV using the plaque reduction assay along with the cytotoxicity to the corresponding cell lines (porcine embryo kidney and Vero). Most of the studied compounds were active against TBEV (EC50 2 to 33 μM) and WNV (EC50 0.15 to 34 μM) and a few also demonstrated inhibitory activity against YFV (EC50 0.18 to 41 μM). To investigate the potential mechanism of action of the synthesized compounds, time‐of‐addition (TOA) experiments and virus yield reduction assays were performed for TBEV. The TOA studies suggested that the antiviral activity of the compounds should affect the early stages of the viral replication cycle after cell entry. Compounds with tetrahydroquinazoline N‐oxide scaffold show a broad spectrum of activity against flaviviruses and represent a promising chemotype for antiviral drug discovery.

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Anti‐Herpes Simplex Virus Type 1 Activity Evaluation of Natural Derived Phloroglucinol Derivatives and Their Molecular Mechanisms Study

Mai,

Li,

Luo

et al. 2023

Chemistry & Biodiversity

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HSV‐1 is a common infection that can cause cold sores. In this study, the anti‐HSV‐1 virus activity of three series compounds A1–A9, B1–B12, C1–C22 was screened by MTT assay, qRT‐PCR assay, Western blot assay and viruses’ plaque assays. The results of MTT assay disclosed that phloroglucinol derivatives C2 and C3 effectively inhibited the death of HSV‐1 infected vero cells with the CC50 values of C2 and C3 were 72.64 μmol/L and 32.62 μmol/L in HaCaT cells, 137.6 μmol/L and 48.55 μmol/L in Hela cells. The IC50 values of C3 in vero cells and Hela cells were 19.26 μmol/L and 22.98 μmol/L, respectively. In the qRT‐PCR experiments, it showed that C2 and C3 effectively reduced the synthesis of HSV‐1 early viral gene VP16 and late viral gene gD. The Western blot results showed that both C2 and C3 inhibited the expression of HSV‐1 gD protein in a concentration‐dependent manner. Lastly, viruses’ plaque assay results showed that C2 and C3 inhibited the production of HSV‐1 progeny virus in Hela cells and HaCaT cells in a concentration‐dependent manner. Taken together, these results suggest that C2 and C3 are promising candidate that warrants further attention in the development of anti‐HSV‐1 drugs.

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

Cited by 14 publications

References 34 publications

Experimental Assessment of Possible Factors Associated with Tick-Borne Encephalitis Vaccine Failure

Experimental Assessment of Possible Factors Associated with Tick-Borne Encephalitis Vaccine Failure

Tetrahydroquinazoline N‐oxide derivatives inhibit reproduction of tick‐borne and mosquito‐borne flaviviruses

Anti‐Herpes Simplex Virus Type 1 Activity Evaluation of Natural Derived Phloroglucinol Derivatives and Their Molecular Mechanisms Study

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