Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

Fanunza, Elisa; Frau, Aldo; Corona, Angela; Tramontano, Enzo

doi:10.1016/bs.armc.2018.08.004

Cited by 13 publications

(11 citation statements)

References 153 publications

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“…The impact of this counteraction is particularly evident for EVD since the fatal outcome has been related to the ability to subvert the type I IFN response that causes the systemic spread of the virus and excessive cytokine production and mediators that lead to the impairment of the vascular system and failure of adaptive immunity [4]. Currently, there is no FDA approved drug or therapy for the treatment of EVD [26]. Several agents have been tested in animal models and some of them have advanced into clinical trials [26].…”

Section: Resultsmentioning

confidence: 99%

“…Currently, there is no FDA approved drug or therapy for the treatment of EVD [26]. Several agents have been tested in animal models and some of them have advanced into clinical trials [26]. The majority of them are directed against viral entry and replication [26].…”

Section: Resultsmentioning

confidence: 99%

“…Several agents have been tested in animal models and some of them have advanced into clinical trials [26]. The majority of them are directed against viral entry and replication [26]. However, an effective alternative strategy for EBOV drug development is the restoration of the host innate response by targeting VP35 and VP24, principal keys of IFN evasion and determinants of virulence.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, two proteins -VP35 and VP24 -are responsible for blocking the IFN production and signaling, respectively, provoking a rapid impairment of the early cellular defense machine [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. In light of their contribution to the high virulence, they are attractive target for drug development [16,18,19,[23][24][25][26]. In this review, we propose an overview of the molecular mechanisms adopted by EBOV to escape this response underling the impact that might has a VP35/VP24 target-based therapy.…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

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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“…EBOV VP35 is a validated drug target for which only a few small molecules have been reported to be active [27, 40, 41], albeit no drug has yet been approved. Here, we present 5 mAbs in scFv format, which are able to react with the Zaire EBOV VP35 protein.…”

Section: Discussionmentioning

confidence: 99%

Intracellular human antibody fragments recognizing the VP35 protein of Zaire Ebola filovirus inhibit the protein activity

et al. 2019

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Background Ebola hemorrhagic fever is caused by the Ebola filovirus (EBOV), which is one of the most aggressive infectious agents known worldwide. The EBOV pathogenesis starts with uncontrolled viral replication and subversion of both the innate and adaptive host immune response. The multifunctional viral VP35 protein is involved in this process by exerting an antagonistic action against the early antiviral alpha/beta interferon (IFN-α/β) response, and represents a suitable target for the development of strategies to control EBOV infection. Phage display technology permits to select antibodies as single chain Fragment variable (scFv) from an artificial immune system, due to their ability to specifically recognize the antigen of interest. ScFv is ideal for genetic manipulation and to obtain antibody constructs useful for targeting either antigens expressed on cell surface or intracellular antigens if the scFv is expressed as intracellular antibody (intrabody) or delivered into the cells. Results Monoclonal antibodies (mAb) in scFv format specific for the EBOV VP35 were isolated from the ETH-2 library of human recombinant antibodies by phage display technology. Five different clones were identified by sequencing, produced in E.coli and expressed in CHO mammalian cells to be characterized in vitro. All the selected scFvs were able to react with recombinant VP35 protein in ELISA, one of the scFvs being also able to react in Western Blot assay (WB). In addition, all scFvs were expressed in cell cytoplasm as intrabodies; a luciferase reporter gene inhibition assay performed in A549 cells showed that two of the scFvs can significantly hamper the inhibition of the IFN-β-induced RIG-I signaling cascade mediated by EBOV VP35. Conclusion Five antibodies in scFv format recognize an active form of EBOV VP35 in ELISA, while one antibody also recognizes VP35 in WB. Two of these scFvs were also able to interfere with the intracellular activity of VP35 in a cell system in vitro. These findings suggest that such antibodies in scFv format might be employed to develop therapeutic molecules able to hamper EBOV infections.

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Monkeypox Outbreak: an Overview of Potential Therapeutic Options

Hassan,

Abdelhamid,

Mohamed

et al. 2023

Curr Treat Options Infect Dis

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Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

Cited by 13 publications

References 153 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

Intracellular human antibody fragments recognizing the VP35 protein of Zaire Ebola filovirus inhibit the protein activity

Monkeypox Outbreak: an Overview of Potential Therapeutic Options

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