0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Marrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Drug development often relies on high-throughput cell-based screening of large compound libraries. However, the lack of miniaturized and parallelized methodologies in chemistry as well as strict separation and incompatibility of the synthesis of bioactive compounds from their biological screenings makes this process expensive and inefficient. Here, we demonstrate an on-chip platform that combines solution-based synthesis of compound libraries with high-throughput biological screenings (chemBIOS). The chemBIOS platform is compatible with both organic solvents required for the synthesis and aqueous solutions necessary for biological screenings. We use the chemBIOS platform to perform 75 parallel, three-component reactions to synthesize a library of lipidoids, followed by characterization via MALDI-MS, on-chip formation of lipoplexes, and on-chip cell screening. The entire process from the library synthesis to cell screening takes only 3 days and about 1 mL of total solutions, demonstrating the potential of the chemBIOS technology to increase efficiency and accelerate screenings and drug development.

          Abstract

          High-throughput cell-based screening of compound libraries is utilised in drug development; however, a lack of compatible methods limits direct synthesis and testing. Here, the authors present a diverse chip based synthesis system which can be combined with cell screening and demonstrate the application.

          Related collections

          Most cited references 24

          • Record: found
          • Abstract: found
          • Article: not found

          Innovation in the pharmaceutical industry: New estimates of R&D costs.

          The research and development costs of 106 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug and biologics development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per approved new compound is $1395 million (2013 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 10.5% yields a total pre-approval cost estimate of $2558 million (2013 dollars). When compared to the results of the previous study in this series, total capitalized costs were shown to have increased at an annual rate of 8.5% above general price inflation. Adding an estimate of post-approval R&D costs increases the cost estimate to $2870 million (2013 dollars).
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The discovery of first-in-class drugs: origins and evolution.

            Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              Can the pharmaceutical industry reduce attrition rates?

                Bookmark

                Author and article information

                Contributors
                levkin@kit.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                28 June 2019
                28 June 2019
                2019
                : 10
                Affiliations
                [1 ]ISNI 0000 0001 0075 5874, GRID grid.7892.4, Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), ; Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
                [2 ]ISNI 0000 0001 0664 9773, GRID grid.59056.3f, Department of Chemistry, , University of Calcutta, ; 92, APC Road, Kolkata, 700009 India
                [3 ]ISNI 0000 0001 0075 5874, GRID grid.7892.4, Karlsruhe Institute of Technology (KIT), Institute of Organic Chemistry (IOC), ; Kaiserstraße 12, 76131 Karlsruhe, Germany
                Article
                10685
                10.1038/s41467-019-10685-0
                6599004
                31253767
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: European Research Council (ERC)
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized

                lipids, high-throughput screening, combinatorial libraries

                Comments

                Comment on this article