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1.
Elife ; 132024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39177307

RESUMEN

Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small Membrane (M) protein plays well-defined roles during viral egress and remains within virion membranes following release and maturation. However, it is unclear whether M plays a functional role in this setting. Here, we show that M forms oligomeric membrane-permeabilising channels in vitro, with increased activity at acidic pH and sensitivity to the prototypic channel-blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements of two trans-membrane domain protomers were shown to comprise more stable assemblages than other oligomers using molecular dynamics (MD) simulations. Models contained a predicted lumenal rimantadine binding site, as well as a second druggable target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to either one site or the other. Hits displayed superior potency in vitro and in cell culture compared with rimantadine, with efficacy demonstrably linked to virion-resident channels. Finally, rimantadine effectively blocked ZIKV viraemia in preclinical models, supporting that M constitutes a physiologically relevant target. This could be explored by repurposing rimantadine, or development of new M-targeted-therapies.

2.
Antiviral Res ; 158: 113-121, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30096339

RESUMEN

Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a virus-coded ion channel or viroporin that was sensitive to the amantadine derivative rimantadine. We now demonstrate that alkylated imino sugars, which have antiviral activity against a number of viruses, inhibit E5 channel activity in vitro. Using molecular modelling we predict that imino sugars intercalate between E5 protomers to prevent channel oligomerisation. We explored the ability of these viroporin inhibitors to block E5-mediated activation of mitogenic signalling in keratinocytes. Treatment with either rimantadine or imino sugars prevented ERK-MAPK phosphorylation and reduced cyclin B1 expression in cells expressing E5 from a number of high-risk HPV types. Moreover, viroporin inhibitors also reduced ERK-MAPK activation and cyclin B1 expression in differentiating primary human keratinocytes containing high-risk HPV18. These observations provide evidence of a key role for E5 viroporin function during the HPV life cycle. Viroporin inhibitors could be utilised for stratified treatment of HPV associated tumours prior to virus integration, or as true antiviral therapies to eliminate virus prior to malignant transformation.


Asunto(s)
Antivirales/farmacología , Iminoazúcares/farmacología , Canales Iónicos/antagonistas & inhibidores , Papillomaviridae/efectos de los fármacos , Línea Celular , Ciclina B1/metabolismo , Humanos , Queratinocitos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Oncogénicas Virales/antagonistas & inhibidores , Infecciones por Papillomavirus/virología , Fosforilación , Rimantadina/farmacología , Transducción de Señal , Proteínas Virales/antagonistas & inhibidores
3.
Int J Mol Sci ; 19(3)2018 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-29562663

RESUMEN

BK polyomavirus (BKPyV; hereafter referred to as BK) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein fail to release from host cells and do not propagate to wild-type levels. Despite this, agnoprotein is not essential for virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-soluble N-ethylmaleimide sensitive fusion (NSF) attachment protein (α-SNAP) is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell.


Asunto(s)
Virus BK/fisiología , Infecciones por Polyomavirus/metabolismo , Proteínas Reguladoras y Accesorias Virales/metabolismo , Animales , Virus BK/genética , Virus BK/ultraestructura , Núcleo Celular/metabolismo , Chlorocebus aethiops , Regulación Viral de la Expresión Génica , Membrana Nuclear/metabolismo , Unión Proteica , Proteínas Solubles de Unión al Factor Sensible a la N-Etilmaleimida/metabolismo , Transcripción Genética , Células Vero , Virión/metabolismo , Virión/ultraestructura
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