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A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase
Viral RNA helicases are involved in duplex unwinding during the RNA replication of the virus. It is suggested that these helicases represent very promising antiviral targets. Viruses of the flaviviridae family are the causative agents of many common and devastating diseases, including hepatitis, yel...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646357/ https://www.ncbi.nlm.nih.gov/pubmed/23678398 http://dx.doi.org/10.7717/peerj.74 |
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author | Vlachakis, Dimitrios Koumandou, Vassiliki Lila Kossida, Sophia |
author_facet | Vlachakis, Dimitrios Koumandou, Vassiliki Lila Kossida, Sophia |
author_sort | Vlachakis, Dimitrios |
collection | PubMed |
description | Viral RNA helicases are involved in duplex unwinding during the RNA replication of the virus. It is suggested that these helicases represent very promising antiviral targets. Viruses of the flaviviridae family are the causative agents of many common and devastating diseases, including hepatitis, yellow fever and dengue fever. As there is currently no available anti-Flaviviridae therapy, there is urgent need for the development of efficient anti-viral pharmaceutical strategies. Herein, we report the complete phylogenetic analysis across flaviviridae alongside a more in-depth evolutionary study that revealed a series of conserved and invariant amino acids that are predicted to be key to the function of the helicase. Structural molecular modelling analysis revealed the strategic significance of these residues based on their relative positioning on the 3D structures of the helicase enzymes, which may be used as pharmacological targets. We previously reported a novel series of highly potent HCV helicase inhibitors, and we now re-assess their antiviral potential using the 3D structural model of the invariant helicase residues. It was found that the most active compound of the series, compound C4, exhibited an IC(50) in the submicromolar range, whereas its stereoisomer (compound C12) was completely inactive. Useful insights were obtained from molecular modelling and conformational search studies via molecular dynamics simulations. C12 tends to bend and lock in an almost “U” shape conformation, failing to establish vital interactions with the active site of HCV. On the contrary, C4 spends most of its conformational time in a straight, more rigid formation that allows it to successfully block the passage of the oligonucleotide in the ssRNA channel of the HCV helicase. This study paves the way and provides the necessary framework for the in-depth analysis required to enable the future design of new and potent anti-viral agents. |
format | Online Article Text |
id | pubmed-3646357 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-36463572013-05-15 A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase Vlachakis, Dimitrios Koumandou, Vassiliki Lila Kossida, Sophia Peerj Bioinformatics Viral RNA helicases are involved in duplex unwinding during the RNA replication of the virus. It is suggested that these helicases represent very promising antiviral targets. Viruses of the flaviviridae family are the causative agents of many common and devastating diseases, including hepatitis, yellow fever and dengue fever. As there is currently no available anti-Flaviviridae therapy, there is urgent need for the development of efficient anti-viral pharmaceutical strategies. Herein, we report the complete phylogenetic analysis across flaviviridae alongside a more in-depth evolutionary study that revealed a series of conserved and invariant amino acids that are predicted to be key to the function of the helicase. Structural molecular modelling analysis revealed the strategic significance of these residues based on their relative positioning on the 3D structures of the helicase enzymes, which may be used as pharmacological targets. We previously reported a novel series of highly potent HCV helicase inhibitors, and we now re-assess their antiviral potential using the 3D structural model of the invariant helicase residues. It was found that the most active compound of the series, compound C4, exhibited an IC(50) in the submicromolar range, whereas its stereoisomer (compound C12) was completely inactive. Useful insights were obtained from molecular modelling and conformational search studies via molecular dynamics simulations. C12 tends to bend and lock in an almost “U” shape conformation, failing to establish vital interactions with the active site of HCV. On the contrary, C4 spends most of its conformational time in a straight, more rigid formation that allows it to successfully block the passage of the oligonucleotide in the ssRNA channel of the HCV helicase. This study paves the way and provides the necessary framework for the in-depth analysis required to enable the future design of new and potent anti-viral agents. PeerJ Inc. 2013-05-07 /pmc/articles/PMC3646357/ /pubmed/23678398 http://dx.doi.org/10.7717/peerj.74 Text en © 2013 Vlachakis et al. http://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Bioinformatics Vlachakis, Dimitrios Koumandou, Vassiliki Lila Kossida, Sophia A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase |
title | A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase |
title_full | A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase |
title_fullStr | A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase |
title_full_unstemmed | A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase |
title_short | A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase |
title_sort | holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of hcv helicase |
topic | Bioinformatics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646357/ https://www.ncbi.nlm.nih.gov/pubmed/23678398 http://dx.doi.org/10.7717/peerj.74 |
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