Cargando…

Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2

Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the l...

Descripción completa

Detalles Bibliográficos
Autores principales: Bollini, Mariela, Leal, Emilse S., Adler, Natalia S., Aucar, María G., Fernández, Gabriela A., Pascual, María J., Merwaiss, Fernando, Alvarez, Diego E., Cavasotto, Claudio N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879447/
https://www.ncbi.nlm.nih.gov/pubmed/29632860
http://dx.doi.org/10.3389/fchem.2018.00079
_version_ 1783311005191766016
author Bollini, Mariela
Leal, Emilse S.
Adler, Natalia S.
Aucar, María G.
Fernández, Gabriela A.
Pascual, María J.
Merwaiss, Fernando
Alvarez, Diego E.
Cavasotto, Claudio N.
author_facet Bollini, Mariela
Leal, Emilse S.
Adler, Natalia S.
Aucar, María G.
Fernández, Gabriela A.
Pascual, María J.
Merwaiss, Fernando
Alvarez, Diego E.
Cavasotto, Claudio N.
author_sort Bollini, Mariela
collection PubMed
description Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC(50) values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals.
format Online
Article
Text
id pubmed-5879447
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-58794472018-04-09 Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2 Bollini, Mariela Leal, Emilse S. Adler, Natalia S. Aucar, María G. Fernández, Gabriela A. Pascual, María J. Merwaiss, Fernando Alvarez, Diego E. Cavasotto, Claudio N. Front Chem Chemistry Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC(50) values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals. Frontiers Media S.A. 2018-03-26 /pmc/articles/PMC5879447/ /pubmed/29632860 http://dx.doi.org/10.3389/fchem.2018.00079 Text en Copyright © 2018 Bollini, Leal, Adler, Aucar, Fernández, Pascual, Merwaiss, Alvarez and Cavasotto. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Bollini, Mariela
Leal, Emilse S.
Adler, Natalia S.
Aucar, María G.
Fernández, Gabriela A.
Pascual, María J.
Merwaiss, Fernando
Alvarez, Diego E.
Cavasotto, Claudio N.
Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2
title Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2
title_full Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2
title_fullStr Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2
title_full_unstemmed Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2
title_short Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2
title_sort discovery of novel bovine viral diarrhea inhibitors using structure-based virtual screening on the envelope protein e2
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879447/
https://www.ncbi.nlm.nih.gov/pubmed/29632860
http://dx.doi.org/10.3389/fchem.2018.00079
work_keys_str_mv AT bollinimariela discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT lealemilses discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT adlernatalias discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT aucarmariag discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT fernandezgabrielaa discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT pascualmariaj discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT merwaissfernando discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT alvarezdiegoe discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2
AT cavasottoclaudion discoveryofnovelbovineviraldiarrheainhibitorsusingstructurebasedvirtualscreeningontheenvelopeproteine2