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Author Correction: Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design.

ABSTRACT: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

SUBMITTER: Shechter S

PROVIDER: S-EPMC6120891 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Author Correction: Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design.

Shechter Sharon S Thomas David R DR Lundberg Lindsay L Pinkham Chelsea C Lin Shih-Chao SC Wagstaff Kylie M KM Debono Aaron A Kehn-Hall Kylene K Jans David A DA

Scientific reports 20180904 1

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. ...[more]

PMID: 30177745

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Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design.

Project description:Therapeutics are currently unavailable for Venezuelan equine encephalitis virus (VEEV), which elicits flu-like symptoms and encephalitis in humans, with an estimated 14% of cases resulting in neurological disease. Here we identify anti-VEEV agents using in silico structure-based-drug-design (SBDD) for the first time, characterising inhibitors that block recognition of VEEV capsid protein (C) by the host importin (IMP) ?/?1 nuclear transport proteins. From an initial screen of 1.5 million compounds, followed by in silico refinement and screening for biological activity in vitro, we identified 21 hit compounds which inhibited IMP?/?1:C binding with IC50s as low as 5?µM. Four compounds were found to inhibit nuclear import of C in transfected cells, with one able to reduce VEEV replication at µM concentration, concomitant with reduced C nuclear accumulation in infected cells. Further, this compound was inactive against a mutant VEEV that lacks high affinity IMP?/?1:C interaction, supporting the mode of its antiviral action to be through inhibiting C nuclear localization. This successful application of SBDD paves the way for lead optimization for VEEV antivirals, and is an exciting prospect to identify inhibitors for the many other viral pathogens of significance that require IMP?/?1 in their infectious cycle.

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Application of <i>In Silico</i> and HTS Approaches to Identify Nuclear Import Inhibitors for Venezuelan Equine Encephalitis Virus Capsid Protein: A Case Study.

Project description:The development of new drugs is costly and time-consuming, with estimates of over $US1 billion and 15 years for a product to reach the market. As understanding of the molecular basis of disease improves, various approaches have been used to target specific molecular interactions in the search for effective drugs. These include high-throughput screening (HTS) for novel drug identification and computer-aided drug design (CADD) to assess the properties of putative drugs before experimental work begins. We have applied conventional HTS and CADD approaches to the problem of identifying antiviral compounds to limit infection by Venezuelan equine encephalitis virus (VEEV). Nuclear targeting of the VEEV capsid (CP) protein through interaction with the host nuclear import machinery has been shown to be essential for viral pathogenicity, with viruses incapable of this interaction being greatly attenuated. Our previous conventional HTS and in silico structure-based drug design (SBDD) screens were successful in identifying novel inhibitors of CP interaction with the host nuclear import machinery, thus providing a unique opportunity to assess the relative value of the two screening approaches directly. This focused review compares and contrasts the two screening approaches, together with the properties of the inhibitors identified, as a case study for parallel use of the two approaches to identify antivirals. The utility of SBDD screens, especially when used in parallel with traditional HTS, in identifying agents of interest to target the host-pathogen interface is highlighted.

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Inhibitors of Venezuelan Equine Encephalitis Virus Identified Based on Host Interaction Partners of Viral Non-Structural Protein 3.

Project description:Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV non-structural protein 3 (nsP3) facilitates cell-specific and virus-specific host factor binding preferences among alphaviruses, thereby providing targets of interest when designing novel antiviral therapeutics. In this study, we utilized an overexpression construct encoding HA-tagged nsP3 to identify host proteins that interact with VEEV nsP3 by mass spectrometry. Bioinformatic analyses of the putative interactors identified 42 small molecules with the potential to inhibit the host interaction targets, and thus potentially inhibit VEEV. Three inhibitors, tomatidine, citalopram HBr, and Z-VEID-FMK, reduced replication of both the TC-83 strain and the Trinidad donkey (TrD) strain of VEEV by at least 10-fold in astrocytoma, astroglial, and microglial cells. Further, these inhibitors reduced replication of the related New World (NW) alphavirus Eastern equine encephalitis virus (EEEV) in multiple cell types, thus demonstrating broad-spectrum antiviral activity. Time-course assays revealed all three inhibitors reduced both infectious particle production and positive-sense RNA levels post-infection. Further evaluation of the putative host targets for the three inhibitors revealed an interaction of VEEV nsP3 with TFAP2A, but not eIF2S2. Mechanistic studies utilizing siRNA knockdowns demonstrated that eIF2S2, but not TFAP2A, supports both efficient TC-83 replication and genomic RNA synthesis, but not subgenomic RNA translation. Overall, this work reveals the composition of the VEEV nsP3 proteome and the potential to identify host-based, broad spectrum therapeutic approaches to treat new world alphavirus infections.

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Project description:Venezuelan equine encephalitis virus (VEEV) is a positive sense, single-stranded RNA virus and member of the New World alphaviruses. It causes a biphasic febrile illness that can be accompanied by central nervous system involvement and moderate morbidity in humans and severe mortality in equines. The virus has a history of weaponization, lacks FDA-approved therapeutics and vaccines in humans, and is considered a select agent. Like other RNA viruses, VEEV replicates in the cytoplasm of infected cells and eventually induces apoptosis. The capsid protein, which contains a nuclear localization and a nuclear export sequence, induces a shutdown of host transcription and nucleocytoplasmic trafficking. Here we show that infection with VEEV causes a dysregulation of cell cycling and a delay in the G0/G1 phase in Vero cells and U87MG astrocytes. Cells infected with VEEV encoding a capsid NLS mutant or treated with the capsid-importin ? interaction inhibitor G281-1485 were partially rescued from this cell cycle dysregulation. Pathway analysis of previously published RNA-sequencing data from VEEV infected U87MG astrocytes identified alterations of canonical pathways involving cell cycle, checkpoint regulation, and proliferation. Multiple cyclins including cyclin D1, cyclin A2 and cyclin E2 and other regulators of the cell cycle were downregulated in infected cells in a capsid NLS dependent manner. Loss of Rb phosphorylation, which is a substrate for cyclin/cdk complexes was also observed. These data demonstrate the importance of capsid nuclear localization and/or importin ? binding for inducing cell cycle arrest and transcriptional downregulation of key cell cycle regulators.

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Characterization of genetic variability of Venezuelan equine encephalitis viruses

Project description:We performed whole genome single nucleotide polymorphism (SNP) based analysis of all available Venezuelan equine encephalitis (VEE) virus antigenic complex genomes and developed a high resolution genome-wide SNP microarray. We used the SNP microarray to analyze a broad panel of VEEV isolates, found excellent concordance between array and sequence based genotypes for previously sequenced strains, and genotyped unsequenced strains.

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Project description:No vaccines or antivirals are approved against Venezuelan equine encephalitis virus (VEEV) infection in humans. To improve our understanding of VEEV-host interactions, we simultaneously profiled host transcriptome and viral RNA (vRNA) in thousands of single cells during infection of human astrocytes. Host transcription was suppressed, and “superproducer cells” with extreme vRNA abundance and altered transcriptome emerged during the first viral life cycle. Cells with increased structural-to-nonstructural transcript ratio demonstrated upregulation of trafficking genes at later time points. Loss- and gain-of-function experiments confirmed pro- and antiviral host factors. Single-cell deep sequencing analysis identified a viral E3 protein mutation altering host gene expression. Lastly, comparison with data from other viruses highlighted common and unique pathways perturbed by infection across evolutionary scales. This study provides a high-resolution characterization of the cellular response to VEEV infection, identifies candidate targets for antivirals, and establishes a comparative single-cell approach to study the evolution of virus-host interactions.

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Postepizootic persistence of Venezuelan equine encephalitis virus, Venezuela.

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