Identification of novel VP35 inhibitors: Virtual screening driven new scaffolds

Ren, Ji-Xia; Zhang, Ruitao; Zhang, Hui; Cao, Xuesong; Liu, Li-Ke; Xie, Yun

doi:10.1016/j.biopha.2016.09.034

Cited by 14 publications

(11 citation statements)

References 18 publications

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“…Although the increasing and constant effort in the identification of VP35 and VP24 inhibitors and despite recent progresses have been made in developing novel techniques to test their functions, nowadays no approved drugs are available against these promising pharmacological targets. These studies involved in vitro, in vivo and in silico approaches aimed to identify potential inhibitors among small molecules and FDA-approved drugs, plant extracts or compounds, oligomers, peptides and immune therapies [16,18,19,63,[102][103][104][105][106][107][108][109][110][111][112][113] Figure 5. VP35 and VP24 inhibitors.…”

Section: Antiviral Approaches To Target Vp35 and Vp24 Ifn Inhibitory mentioning

confidence: 99%

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

Fanunza

Frau

Corona

et al. 2019

IDDT

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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.

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Section: Antiviral Approaches To Target Vp35 and Vp24 Ifn Inhibitory mentioning

confidence: 99%

“…Seven new VP35 potential inhibitors (cpd 1 -7) were identified using a pharmacophore model (HypoA of 4acetyl-3-hydroxy-1-phenyl-1H-pyrrol-2(5H)-one derivates) with 3D QSAR prediction and molecular docking method [104].…”

Section: Small Molecules and Fda Approved Drugsmentioning

confidence: 99%

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

Fanunza

Frau

Corona

et al. 2019

IDDT

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“…Finally, it is worth noting that most VP35 inhibitors reported so far act differently, binding to a pocket formed by residues from the α-helical and β-sheet subdomains including Ala221, Arg225, Gln241, Biochemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 18 Leu242, Lys248, Lys251, Pro293, Ile295, Ile297, Asp302, and Phe328 which is reported to be important for NP interaction 28, 101,102 . Considering that the VP35 pocket binding to dsRNA has also been involved with the interaction with other cellular factors such as PACT, IKK-ε and TBK-1 along the RIG-I pathway, as well as with other EBOV proteins such as NP, these results may suggest that small molecules interacting with this pocket could also be able to have multiple effects, impairing other VP35 functions in addition to its IFN antagonism.…”

Section: Figure 4 [A]mentioning

confidence: 99%

Identification of Myricetin as an Ebola Virus VP35–Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay

et al. 2018

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Ebola virus (EBOV) is a filovirus that causes a severe and rapidly progressing hemorrhagic syndrome whose recent epidemic enlightened the urgent need of novel therapeutic agents, since no drug is currently approved. A key contribution to the high lethality observed during EBOV outbreaks comes from viral evasion of the host antiviral innate immune response in which the viral protein VP35 plays a crucial role, blocking the interferon type I production, firstly by masking the viral dsRNA and preventing its detection by the pattern recognition receptor RIG-I. Aiming to identify inhibitors of VP35 interaction with the viral dsRNA, counteracting the VP35 viral innate immune evasion, we established a new methodology for high-yield recombinant VP35 (rVP35) expression and purification, and a novel and robust fluorescence-based rVP35-RNA interaction assay (Z'-factor of 0.69). Taking advantage of such newlyestablished methods, we screened a small library of Sardinian natural extracts finding Limonium morisianum as the most potent inhibitor extract. A bio-guided fractionation led to the identification of myricetin as the component able to inhibit rVP35-dsRNA interaction with an IC 50 value of 2.7 µM.Molecular docking studies showed that myricetin interacts with the highly conserved region of the VP35 RNA binding domain, laying the basis for further structural optimization of potent VP35-dsRNA inhibitors.

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“…In contrast, Kirchdoerfer and colleagues show that monomeric NP has no significant affinity for RNA, suggesting that the NPBP peptide would be displaced by an additional NP molecule, causing NP oligomerisation that would then allow for RNA binding. However, in either process, VP35–NP interactions are crucial for virus replication and are being explored as targets for future therapeutics [ 41 , 42 ].…”

Section: Vp35mentioning

confidence: 99%

Ebolaviruses: New roles for old proteins

Cantoni

Rossman

2018

PLoS Negl Trop Dis

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In 2014, the world witnessed the largest Ebolavirus outbreak in recorded history. The subsequent humanitarian effort spurred extensive research, significantly enhancing our understanding of ebolavirus replication and pathogenicity. The main functions of each ebolavirus protein have been studied extensively since the discovery of the virus in 1976; however, the recent expansion of ebolavirus research has led to the discovery of new protein functions. These newly discovered roles are revealing new mechanisms of virus replication and pathogenicity, whilst enhancing our understanding of the broad functions of each ebolavirus viral protein (VP). Many of these new functions appear to be unrelated to the protein’s primary function during virus replication. Such new functions range from bystander T-lymphocyte death caused by VP40-secreted exosomes to new roles for VP24 in viral particle formation. This review highlights the newly discovered roles of ebolavirus proteins in order to provide a more encompassing view of ebolavirus replication and pathogenicity.

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Identification of novel VP35 inhibitors: Virtual screening driven new scaffolds

Cited by 14 publications

References 18 publications

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

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

Identification of Myricetin as an Ebola Virus VP35–Double-Stranded RNA Interaction Inhibitor through a Novel Fluorescence-Based Assay

Ebolaviruses: New roles for old proteins

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