12
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      From carbohydrate leads to glycomimetic drugs

      ,

      Nature Reviews. Drug Discovery

      Nature Publishing Group UK

      Read this article at

      ScienceOpenPublisherPMC
      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.

          Key Points

          • Carbohydrates coat the surfaces of all cells and most proteins. They contain molecular information used in recognition events with carbohydrate-binding proteins (such as the lectin families) that decode this information. These bioactive carbohydrates open up a new source of novel targets for drug development.

          • Although carbohydrates have prominent roles in a wide range of biological processes, the currently approved drugs are mainly glycosidase inhibitors and sulphated glycosaminoglycans (that is, heparin).

          • Current preclinical research on lectins that are found in humans and pathogens indicates that glycomimetics could provide an alternative strategy for the treatment of inflammatory diseases (by targeting selectins) and infectious diseases (by targeting dendritic cell-specific ICAM3-grabbing non-integrin 1 (DC-SIGN), FimH, PA-I galactophilic lectin (PA-IL) and fructose-binding PA-IIL lectins).

          • In general, carbohydrates lack drug-like properties such as high affinity or adequate bioavailability and therapeutically relevant plasma half-lives. In addition, their large-scale production is cumbersome and expensive. When developing this class of drugs, the goal is to mimic the biological information of a functional carbohydrate with a glycomimetic that overcomes these challenges and has appropriate pharmacodynamic and pharmacokinetic properties.

          Abstract

          Cell surface carbohydrates and carbohydrate-binding proteins mediate many key recognition events. This article reviews current progress in the development of glycomimetics and the opportunities and challenges presented by this relatively untapped source of therapeutics.

          Abstract

          Carbohydrates are the most abundant natural products. Besides their role in metabolism and as structural building blocks, they are fundamental constituents of every cell surface, where they are involved in vital cellular recognition processes. Carbohydrates are a relatively untapped source of new drugs and therefore offer exciting new therapeutic opportunities. Advances in the functional understanding of carbohydrate–protein interactions have enabled the development of a new class of small-molecule drugs, known as glycomimetics. These compounds mimic the bioactive function of carbohydrates and address the drawbacks of carbohydrate leads, namely their low activity and insufficient drug-like properties. Here, we examine examples of approved carbohydrate-derived drugs, discuss the potential of carbohydrate-binding proteins as new drug targets (focusing on the lectin families) and consider ways to overcome the challenges of developing this unique class of novel therapeutics.

          Related collections

          Most cited references 171

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

          Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors

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

            Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.

            Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. Here, we demonstrate that ICAM-3 expressed by resting T cells is important in this first contact with DC. We discovered that instead of the common ICAM-3 receptors LFA-1 and alphaDbeta2, a novel DC-specific C-type lectin, DC-SIGN, binds ICAM-3 with high affinity. DC-SIGN, which is abundantly expressed by DC both in vitro and in vivo, mediates transient adhesion with T cells. Since antibodies against DC-SIGN inhibit DC-induced proliferation of resting T cells, our findings predict that DC-SIGN enables T cell receptor engagement by stabilization of the DC-T cell contact zone.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells

              Dengue virus is a single-stranded, enveloped RNA virus that productively infects human dendritic cells (DCs) primarily at the immature stage of their differentiation. We now find that all four serotypes of dengue use DC-SIGN (CD209), a C-type lectin, to infect dendritic cells. THP-1 cells become susceptible to dengue infection after transfection of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), or its homologue L-SIGN, whereas the infection of dendritic cells is blocked by anti–DC-SIGN antibodies and not by antibodies to other molecules on these cells. Viruses produced by dendritic cells are infectious for DC-SIGN– and L-SIGN–bearing THP-1 cells and other permissive cell lines. Therefore, DC-SIGN may be considered as a new target for designing therapies that block dengue infection.
                Bookmark

                Author and article information

                Contributors
                beat.ernst@unibas.ch
                Journal
                Nat Rev Drug Discov
                Nat Rev Drug Discov
                Nature Reviews. Drug Discovery
                Nature Publishing Group UK (London )
                1474-1776
                1474-1784
                24 July 2009
                2009
                : 8
                : 8
                : 661-677
                Affiliations
                GRID grid.6612.3, ISNI 0000 0004 1937 0642, Institute of Molecular Pharmacy, University of Basel, ; Klingelbergstrasse 50, Basel, CH-4056 Switzerland
                Article
                BFnrd2852
                10.1038/nrd2852
                7097102
                19629075
                © Nature Publishing Group 2009

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2009

                Comments

                Comment on this article