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Artículo

Structure-based drug design for envelope protein E2 uncovers a new class of bovine viral diarrhea inhibitors that block virus entry

Pascual, María JoséIcon ; Merwaiss, FernandoIcon ; Leal, Emilse SoledadIcon ; Quintana, Maria EugeniaIcon ; Capozzo, Alejandra VictoriaIcon ; Cavasotto, Claudio NorbertoIcon ; Bollini, MarielaIcon ; Alvarez, Diego EzequielIcon
Fecha de publicación: 01/2018
Editorial: Elsevier Science
Revista: Antiviral Research
ISSN: 0166-3542
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Virología

Resumen

Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. Here, we took a computer-guided approach with the aim of identifying new antivirals against the envelope protein E2 of bovine viral diarrhea virus (BVDV). BVDV is an enveloped virus with an RNA genome responsible for major economic losses of the cattle industry worldwide. Based on the crystal structure of the envelope protein E2, we defined a binding site at the interface of the two most distal domains from the virus membrane and pursued a hierarchical docking-based virtual screening search to identify small-molecule ligands of E2. Phenyl thiophene carboxamide derivative 12 (PTC12) emerged as a specific inhibitor of BVDV replication from in vitro antiviral activity screening of candidate molecules, displaying an IC 50 of 0.30 μM against the reference NADL strain of the virus. Using reverse genetics we constructed a recombinant BVDV expressing GFP that served as a sensitive reporter for the study of the mechanism of action of antiviral compounds. Time of drug addition assays showed that PTC12 inhibited an early step of infection. The mechanism of action was further dissected to find that the compound specifically acted at the internalization step of virus entry. Interestingly, we demonstrated that similar to PTC12, the benzimidazole derivative 03 (BI03) selected in the virtual screen also inhibited internalization of BVDV. Furthermore, docking analysis of PTC12 and BI03 into the binding site revealed common interactions with amino acid residues in E2 suggesting that both compounds could share the same molecular target. In conclusion, starting from a targeted design strategy of antivirals against E2 we identified PTC12 as a potent inhibitor of BVDV entry. The compound can be valuable in the design of antiviral strategies in combination with already well-characterized polymerase inhibitors of BVDV.
Palabras clave: ANTIVIRALS , BVDV , DOCKING , PESTIVIRUS , REPORTER VIRUS , VIRTUAL SCREENING
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/86212
URL: https://www.sciencedirect.com/science/article/pii/S0166354217305983
DOI: http://dx.doi.org/10.1016/j.antiviral.2017.10.010
Colecciones
Articulos(SEDE CENTRAL) [31609]
Articulos de SEDE CENTRAL
Articulos(IIB-INTECH) [759]
Articulos de INST.DE INVEST.BIOTECNOLOGICAS - INSTITUTO TECNOLOGICO CHASCOMUS
Articulos(CIBION) [166]
Articulos de CENTRO DE INVESTIGACIONES EN BIONANOCIENCIAS "ELIZABETH JARES ERIJMAN"
Articulos(IBIOBA - MPSP) [190]
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Citación
Pascual, María José; Merwaiss, Fernando; Leal, Emilse Soledad; Quintana, Maria Eugenia; Capozzo, Alejandra Victoria; et al.; Structure-based drug design for envelope protein E2 uncovers a new class of bovine viral diarrhea inhibitors that block virus entry; Elsevier Science; Antiviral Research; 149; 1-2018; 179-190
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