Many plants have been used in traditional medicine for their antibacterial, antifungal, antiprotozoal, antiviral, antidiarrhoeal, analgesic, antimalarial, antioxidant, anti-inflammatory and anticancer activities. In order to find novel antimicrobial and antiviral agents, the aim of the present study was the evaluation of the antibacterial and antibiofilm susceptibility of Asphodelus microcarpus leaves extract. Moreover, the antiviral activity and the phytochemical composition of the active extract were also determined. Antimicrobial and antibiofilm activities of leaves ethanol extract of A. microcarpus were evaluated on 13 different microbial strains. We selected three different sets of microorganisms: (i) Gram-positive bacteria, (ii) Gram-negative bacteria and (iii) yeasts. The potential antiviral activity of A. microcarpus leaves ethanol extract was evaluated with a luciferase reporter gene assay in which the dsRNA-dependent RIG-I-mediated IFN-β activation was inducted or inhibited by the Ebola virus VP35 protein. HPLC-DAD-MS was used to identify phenolic profile of the active extract. A. microcarpus leaves extract showed a potent inhibitory activity on Gram-positive bacteria while only a reduced inhibition was observed on Gram-negative bacteria. No activity was detected against Yeasts. The extract also showed an interesting antibiofilm motif on various bacterial strains (E. coli, S. aureus, S. haemolyticus and B. clausii). Moreover, this extract significantly affected the Ebola virus VP35 inhibition of the viral RNA (vRNA) induced IFN response. The overall results provide supportive data on the use of A. microcarpus as antimicrobial agent and a potential source of anti-viral natural products. Data collected set the bases for further studies for the identification of single active components and the development of new pharmaceuticals.

/pdf/broad-range-potential-of-asphodelus-microcarpus-leaves-4wzllhvaaa.pdf

Broad-range potential of Asphodelus microcarpus leaves extract for drug development.

The template for Ebola virus (EBOV) transcription and replication is the helical viral nucleocapsid composed of the viral negative-sense (−) RNA genome, which is complexed by the nucleoprotein (NP), VP35, polymerase L, VP24, and VP30. While viral replication is exerted by polymerase L and its cofactor VP35, EBOV mRNA synthesis is regulated by the viral nucleocapsid protein VP30, an essential EBOV-specific transcription factor. VP30 is a homohexameric phosphoprotein containing a nonconventional zinc finger. The transcriptional support activity of VP30 is strongly influenced by its phosphorylation state. We studied here how RNA binding contributed to VP309s function in transcriptional activation. Using a novel mobility shift assay and the 3′-terminal 154 nucleotides of the EBOV genome as a standard RNA substrate, we detected that RNA binding of VP30 was severely impaired by VP30 mutations that (i) destroy the protein9s capability to form homohexamers, (ii) disrupt the integrity of its zinc finger domain, (iii) mimic its fully phosphorylated state, or (iv) alter the putative RNA binding region. RNA binding of the mutant VP30 proteins correlated strongly with their transcriptional support activity. Furthermore, we showed that the interaction between VP30 and the polymerase cofactor VP35 is RNA dependent, while formation of VP30 homohexamers and VP35 homotetramers is not. Our data indicate that RNA binding of VP30 is essential for its transcriptional support activity and stabilizes complexes of VP35/L polymerase with the (−) RNA template to favor productive transcriptional initiation in the presence of termination-active RNA secondary structures. IMPORTANCE Ebola virus causes severe fevers with unusually high case fatality rates. The recent outbreak of Ebola virus in West Africa claimed more than 11,000 lives and threatened to destabilize a whole region because of its dramatic effects on the public health systems. It is currently not completely understood how Ebola virus manages to balance viral transcription and replication in the infected cells. This study shows that transcriptional support activity of the Ebola virus transcription factor VP30 is highly correlated with its ability to bind viral RNA. The interaction between VP30 and VP35, the Ebola virus polymerase cofactor, is dependent on the presence of RNA as well. Our data contribute to the understanding of the dynamic interplay between nucleocapsid proteins and the viral RNA template in order to promote viral RNA synthesis.

/pdf/rna-binding-of-ebola-virus-vp30-is-essential-for-activating-3s20d2vrwm.pdf

RNA Binding of Ebola Virus VP30 Is Essential for Activating Viral Transcription

Ebola virus (EBOV) is a non-segmented, negative-sense RNA virus (NNSV) in the family Filoviridae, and is recognized as one of the most lethal pathogens in the planet. For RNA viruses, cellular or virus-encoded RNA helicases play pivotal roles in viral life cycles by remodelling viral RNA structures and/or unwinding viral dsRNA produced during replication. However, no helicase or helicase-like activity has ever been found to associate with any NNSV-encoded proteins, and it is unknown whether the replication of NNSVs requires the participation of any viral or cellular helicase. Here, we show that despite of containing no conserved NTPase/helicase motifs, EBOV VP35 possesses the NTPase and helicase-like activities that can hydrolyse all types of NTPs and unwind RNA helices in an NTP-dependent manner, respectively. Moreover, guanidine hydrochloride, an FDA-approved compound and inhibitor of certain viral helicases, inhibited the NTPase and helicase-like activities of VP35 as well as the replication/transcription of an EBOV minigenome replicon in cells, highlighting the importance of VP35 helicase-like activity during EBOV life cycle. Together, our findings provide the first demonstration of the NTPase/helicase-like activity encoded by EBOV, and would foster our understanding of EBOV and NNSVs.

Ebola virus VP35 has novel NTPase and helicase-like activities

Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. The etiological agent of the Ebola Virus Disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation. Particularly, the efficacious suppression of the IFN cascade contributes to disease progression and severity. Among the EBOVencoded proteins, the Viral Proteins 35 (VP35) and 24 (VP24) are responsible for the EBOV extreme virulence, representing the core of such inhibitory function through which EBOV determines its very effective shield to the cellular immune defenses. VP35 inhibits the activation of the cascade leading to IFN production, while VP24 inhibits the activation of the IFN-stimulated genes. A number of studies demonstrated that both VP35 and VP24 is validated target for drug development. Insights into the structural characteristics of VP35 and VP24 domains revealed crucial pockets exploitable for drug development. Considered the lack of therapy for EVD, restoring the immune activation is a promising approach for drug development. In the present review, we summarize the importance of VP35 and VP24 proteins in counteracting the host IFN cellular response and discuss their potential as druggable viral targets as a promising approach toward attenuation of EBOV virulence.

/pdf/insights-into-ebola-virus-vp35-and-vp24-interferon-1pg3gwdaqj.pdf

Insights into Ebola Virus VP35 and VP24 Interferon Inhibitory Functions and their Initial Exploitation as Drug Targets

Structures of Ebola and Reston Virus VP35 Oligomerization Domains and Comparative Biophysical Characterization in All Ebolavirus Species.

dsRNA binding characterization of full length recombinant wild type and mutants Zaire ebolavirus VP35.

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dsRNA binding characterization of full length recombinant wild type and mutants Zaire ebolavirus VP35.