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      Daptomycin, a last-resort antibiotic, binds ribosomal protein S19 in humans

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          Abstract

          Background

          Daptomycin is a recently introduced, last-resort antibiotic that displays a unique mode of action against Gram-positive bacteria that is not fully understood. Several bacterial targets have been proposed but no human binding partner is known.

          Methods

          In the present study we tested daptomycin in cell viability and proliferation assays against six human cell lines, describe the synthesis of biotinylated and fluorescently labeled analogues of daptomycin. Biotinylated daptomycin was used as bait to isolate the human binding partner by the application of reverse chemical proteomics using T7 phage display of five human tumor cDNA libraries. The interaction between the rescued protein and daptomycin was validated via siRNA knockdown, DARTS assay and immunocytochemistry.

          Results

          We have found that daptomycin possesses selective growth inhibition of some cancer cell lines, especially MCF7. The unbiased interrogation of human cDNA libraries, displayed on bacteriophage T7, revealed a single human target of daptomycin; ribosomal protein S19. Using a drug affinity responsive target stability (DARTS) assay in vitro, we show that daptomycin stabilizes RPS19 toward pronase. Fluorescently labeled daptomycin stained specific structures in HeLa cells and co-localized with a RPS19 antibody.

          Conclusion

          This study provides, for the first time, a human protein target of daptomycin and identifies RPS19 as a possible anticancer drug target for the development of new pharmacological applications and research.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12953-017-0124-2) contains supplementary material, which is available to authorized users.

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          Most cited references 47

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          How many drug targets are there?

          For the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.
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            Cu-catalyzed azide-alkyne cycloaddition.

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              Global mapping of pharmacological space.

              We present the global mapping of pharmacological space by the integration of several vast sources of medicinal chemistry structure-activity relationships (SAR) data. Our comprehensive mapping of pharmacological space enables us to identify confidently the human targets for which chemical tools and drugs have been discovered to date. The integration of SAR data from diverse sources by unique canonical chemical structure, protein sequence and disease indication enables the construction of a ligand-target matrix to explore the global relationships between chemical structure and biological targets. Using the data matrix, we are able to catalog the links between proteins in chemical space as a polypharmacology interaction network. We demonstrate that probabilistic models can be used to predict pharmacology from a large knowledge base. The relationships between proteins, chemical structures and drug-like properties provide a framework for developing a probabilistic approach to drug discovery that can be exploited to increase research productivity.
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                Author and article information

                Contributors
                michael.gotsbacher@sydney.edu.au
                sungmincho@yonsei.ac.kr
                +82-2 2123-5883 , kwonhj@yonsei.ac.kr
                +61-2 9850-8290 , peter.karuso@mq.edu.au
                Journal
                Proteome Sci
                Proteome Sci
                Proteome Science
                BioMed Central (London )
                1477-5956
                1 July 2017
                1 July 2017
                2016
                : 15
                Affiliations
                [1 ]ISNI 0000 0001 2158 5405, GRID grid.1004.5, Department of Chemistry and Biomolecular Sciences, , Macquarie University, ; Sydney, NSW 2109 Australia
                [2 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Biotechnology, , Yonsei University, ; 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749 South Korea
                [3 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, , Present address: School of Medical Sciences (Pharmacology), The University of Sydney, ; Sydney, NSW 2006 Australia
                124
                10.1186/s12953-017-0124-2
                5494143
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000923, Australian Research Council;
                Award ID: DP130103281
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;
                Award ID: 2015K1A1A2028365
                Award ID: 2015M3A9C4076321
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Molecular biology

                darts, phage display, reverse chemical proteomics, daptomycin

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