Dataset Information

Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo.

ABSTRACT: Vaccines and antivirals to combat dengue, Zika, and other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses and the propensity of non-neutralizing, cross-reactive antibodies to facilitate cellular infection and increase disease severity. As an alternative, direct-acting antivirals targeting the flavivirus envelope protein, E, have the potential to act via an analogous mode of action without the risk of antibody-dependent enhancement of infection and disease. We previously discovered that structurally diverse small molecule inhibitors of the dengue virus E protein exhibit varying levels of antiviral activity against other flaviviruses in cell culture. Here, we demonstrate that the broad-spectrum activity of several cyanohydrazones against dengue, Zika, and Japanese encephalitis viruses is due to specific inhibition of E-mediated membrane fusion during viral entry and provide proof of concept for pharmacological inhibition of E as an antiviral strategy in vivo.

SUBMITTER: Li PC

PROVIDER: S-EPMC6548335 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo.

Li Pi-Chun PC Jang Jaebong J Hsia Chih-Yun CY Groomes Patrice V PV Lian Wenlong W de Wispelaere Melissanne M Pitts Jared D JD Wang Jinhua J Kwiatkowski Nicholas N Gray Nathanael S NS Yang Priscilla L PL

ACS infectious diseases 20190114 3

Vaccines and antivirals to combat dengue, Zika, and other flavivirus pathogens present a major, unmet medical need. Vaccine development has been severely challenged by the antigenic diversity of these viruses and the propensity of non-neutralizing, cross-reactive antibodies to facilitate cellular infection and increase disease severity. As an alternative, direct-acting antivirals targeting the flavivirus envelope protein, E, have the potential to act via an analogous mode of action without the r ...[more]

PMID: 30608640

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Project description:BACKGROUND:With the emergence of new influenza virus strains that are resistant to current inhibitors such as oseltamivir (anti-neuraminidase (NA)) and amantadine (anti-M2 proton channel), influenza A viruses continue to be a serious threat to the public health worldwide. With this in view, there is a persistent need for the development of broader and more effective vaccines and therapeutics. Identification of broadly neutralizing antibodies (bNAbs) that recognize relatively invariant structures ?on influenza haemagglutinin (HA) stem has invigorated efforts to develop universal influenza vaccines. AIM:The current computational study is designed to identify potential flavonoid inhibitors that bind to the contact epitopes of HA stem that are targeted by broadly neutralizing antibodies (bNAb). METHOD:In this study, we utilized the three-dimensional crystallographic structure of different HA subtypes (H1, H2, H5, H3, and H7) in complex with bNAb to screen for potential broadly reactive influenza inhibitors. We performed Quantitative Structure-Activity and Relationship (QSAR) for 100 natural compounds known for their antiviral activity and performed molecular docking using AutoDock 4.2 suite. Furthermore, we conducted virtual screening of 1413 bioassay hit compounds by using virtual lab bench CLC Drug Discovery. RESULTS:The results showed 18 lead flavonoids with strong binding abilities to bNAb epitopes of various HA subtypes. These 18 broadly reactive compounds exhibited significant interactions with an average of seven Hbonds, docking energy of -22.43 kcal·mol-1, and minimum interaction ? energy of -4.65 kcal·mol-1, with functional contact residues. Procyanidin depicted strong interactions with group 1 HAs, whereas both sorbitol and procyanidin exhibited significant interactions with group 2 HAs. CONCLUSION:Using in silico docking analysis, we identified 18 bioactive flavonoids with potential strong binding cababilities to influenza HA-stems of various subtypes, which are the target for bNAb. The virtual screened bioassay hit compounds depicted a high number of Hbonds but low interaction and docking values compared to antiviral flavonoids. Using structure-based design and nanotechnology-based approaches, identified molecules could be modified to generate next generation anti-influenza drugs.

Dataset Information

Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo.

Publications

Small Molecules Targeting the Flavivirus E Protein with Broad-Spectrum Activity and Antiviral Efficacy in Vivo.

Similar Datasets

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