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Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase

Hepatitis E Virus (HEV) is a quasi-enveloped virus having a single-stranded, positive-sense RNA genome (~7.2 kb), flanked with a 5′ methylated cap and a 3′ polyadenylated tail. The HEV open reading frame 1 (ORF1) encodes a 186-kDa polyprotein speculated to get processed and produce Methyltransferase...

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Autores principales: Hooda, Preeti, Chaudhary, Meenakshi, Parvez, Mohammad K., Sinha, Neha, Sehgal, Deepak
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415367/
https://www.ncbi.nlm.nih.gov/pubmed/36016400
http://dx.doi.org/10.3390/v14081778
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author Hooda, Preeti
Chaudhary, Meenakshi
Parvez, Mohammad K.
Sinha, Neha
Sehgal, Deepak
author_facet Hooda, Preeti
Chaudhary, Meenakshi
Parvez, Mohammad K.
Sinha, Neha
Sehgal, Deepak
author_sort Hooda, Preeti
collection PubMed
description Hepatitis E Virus (HEV) is a quasi-enveloped virus having a single-stranded, positive-sense RNA genome (~7.2 kb), flanked with a 5′ methylated cap and a 3′ polyadenylated tail. The HEV open reading frame 1 (ORF1) encodes a 186-kDa polyprotein speculated to get processed and produce Methyltransferase (MTase), one of the four essential replication enzymes. In this study, we report the identification of the MTase inhibitor, which may potentially deplete its enzymatic activity, thus causing the cessation of viral replication. Using in silico screening through docking, we identified ten putative compounds, which were tested for their anti-MTase activity. This resulted in the identification of 3-(4-Hydroxyphenyl)propionic acid (HPPA), with an IC(50) value of 0.932 ± 0.15 μM, which could be perceived as an effective HEV inhibitor. Furthermore, the compound was tested for inhibition of HEV replication in the HEV culture system. The viral RNA copies were markedly decreased from ~3.2 × 10(6) in untreated cells to ~4.3 × 10(2.8) copies in 800 μM HPPA treated cells. Therefore, we propose HPPA as a potential drug-like inhibitor against HEV-MTase, which would need further validation through in vivo analysis using animal models and the administration of Pharmacokinetic and Pharmacodynamic (PK/PD) studies.
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spelling pubmed-94153672022-08-27 Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase Hooda, Preeti Chaudhary, Meenakshi Parvez, Mohammad K. Sinha, Neha Sehgal, Deepak Viruses Article Hepatitis E Virus (HEV) is a quasi-enveloped virus having a single-stranded, positive-sense RNA genome (~7.2 kb), flanked with a 5′ methylated cap and a 3′ polyadenylated tail. The HEV open reading frame 1 (ORF1) encodes a 186-kDa polyprotein speculated to get processed and produce Methyltransferase (MTase), one of the four essential replication enzymes. In this study, we report the identification of the MTase inhibitor, which may potentially deplete its enzymatic activity, thus causing the cessation of viral replication. Using in silico screening through docking, we identified ten putative compounds, which were tested for their anti-MTase activity. This resulted in the identification of 3-(4-Hydroxyphenyl)propionic acid (HPPA), with an IC(50) value of 0.932 ± 0.15 μM, which could be perceived as an effective HEV inhibitor. Furthermore, the compound was tested for inhibition of HEV replication in the HEV culture system. The viral RNA copies were markedly decreased from ~3.2 × 10(6) in untreated cells to ~4.3 × 10(2.8) copies in 800 μM HPPA treated cells. Therefore, we propose HPPA as a potential drug-like inhibitor against HEV-MTase, which would need further validation through in vivo analysis using animal models and the administration of Pharmacokinetic and Pharmacodynamic (PK/PD) studies. MDPI 2022-08-15 /pmc/articles/PMC9415367/ /pubmed/36016400 http://dx.doi.org/10.3390/v14081778 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hooda, Preeti
Chaudhary, Meenakshi
Parvez, Mohammad K.
Sinha, Neha
Sehgal, Deepak
Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase
title Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase
title_full Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase
title_fullStr Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase
title_full_unstemmed Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase
title_short Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase
title_sort inhibition of hepatitis e virus replication by novel inhibitor targeting methyltransferase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415367/
https://www.ncbi.nlm.nih.gov/pubmed/36016400
http://dx.doi.org/10.3390/v14081778
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