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      Open drug discovery for the Zika virus

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          The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks.

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          Most cited references 58

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          The SWISS-MODEL Repository and associated resources

          SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) is a database of 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for all sequences in Swiss-Prot and for relevant models organisms. Regular updates ensure that target coverage is complete, that models are built using the most recent sequence and template structure databases, and that improvements in the underlying modelling pipeline are fully utilised. As of September 2008, the database contains 3.4 million entries for 2.7 million different protein sequences from the UniProt database. SWISS-MODEL Repository allows the users to assess the quality of the models in the database, search for alternative template structures, and to build models interactively via SWISS-MODEL Workspace (http://swissmodel.expasy.org/workspace/). Annotation of models with functional information and cross-linking with other databases such as the Protein Model Portal (http://www.proteinmodelportal.org) of the PSI Structural Genomics Knowledge Base facilitates the navigation between protein sequence and structure resources.
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            Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses.

             G Kuno,  F. Chang (2006)
            Many members of the genus Flavivirus are the agents of important diseases of humans, livestock, and wildlife. Currently, no complete genome sequence is available for the three African viruses, Bagaza, Zika, and Kedougou viruses, each representing a distinct virus subgroup according to the latest virus classification. In this study, we obtained a complete genome sequence of each of those three viruses and characterized the open reading frames (ORFs) with respect to gene sizes, cleavage sites, potential glycosylation sites, distribution of cysteine residues, and unique motifs. The sequences of the three viruses were then scanned across the entire length of the ORF against available sequences of other African flaviviruses and selected reference viruses for genetic relatedness. The data collectively indicated that Kedougou virus was close to dengue viruses but nonetheless distinct, while Bagaza virus shared genetic relatedness with West Nile virus in several genomic regions. In the non-coding regions, it was found that a particular organizational pattern of conserved sequences in the 3' terminal region generally correlated with the current virus grouping.
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              Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013.

               E Oehler,  L Watrin,  P Larre (2014)
              Zika fever, considered as an emerging disease of arboviral origin, because of its expanding geographic area, is known as a benign infection usually presenting as an influenza-like illness with cutaneous rash. So far, Zika virus infection has never led to hospitalisation. We describe the first case of Guillain-Barré syndrome (GBS) occurring immediately after a Zika virus infection, during the current Zika and type 1 and 3 dengue fever co-epidemics in French Polynesia.

                Author and article information

                F1000Research (London, UK )
                9 February 2016
                : 5
                [1 ]Collaborations in Chemistry Inc, Fuquay-Varina, NC, USA
                [2 ]Collaborations Pharmaceuticals Inc., Fuquay-Varina, NC, USA
                [3 ]Collaborative Drug Discovery Inc., Burlingame, CA, USA
                [4 ]Open Knowledge Foundation Deutschland e.V., Berlin, Germany
                [5 ]The International Rescue Committee , NY, NY, USA
                [6 ]Department of Pharmacology, Physiology and Neuroscience, Rutgers University-New Jersey Medical School, Newark, NJ, USA
                [7 ]Division of Infectious Diseases, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University–New Jersey Medical School, Newark, NJ, USA
                [8 ]Chemical Biology and Screening Platform, Brazilian Laboratory of Biosciences (LNBio), CNPEM, Campinas, Brazil
                [9 ]Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
                [10 ]Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA
                [11 ]ChemConnector, Wake Forest, NC, USA
                [12 ]LabMol - Laboratory for Molecular Modeling and Drug Design, Faculty of Pharmacy, Federal University of Goias, Goiânia, Brazil
                [1 ]Department of Antiviral Research, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA
                [1 ]JL3Pharma LLC, Stonington, USA
                [1 ]Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
                Author notes

                All authors contributed to the collaborative writing of this project.

                Competing interests: S.E. works for Collaborations in Chemistry, Collaborations Pharmaceuticals, Inc. and Collaborative Drug Discovery, Inc.

                D.M. is a contractor for the National Center for Biotechnology Information.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Copyright: © 2016 Ekins S et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: PVE-CNPq
                Award ID: 313727/2014-7
                EM is currently Special Visiting Professor in Federal University of Goias - Brazil (PVE-CNPq, grant #313727/2014-7).
                I confirm that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Opinion Article
                Drug Discovery & Design
                Tropical & Travel-Associated Diseases


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