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Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends

Independent Researcher, 1326 Spruce Street Suite 706, Philadephia, PA 19107, USA
Medicines 2019, 6(3), 80; https://doi.org/10.3390/medicines6030080
Received: 16 June 2019 / Revised: 16 July 2019 / Accepted: 18 July 2019 / Published: 29 July 2019
(This article belongs to the Special Issue Application of Glycobiology in the Treatment of Diseases)
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Abstract

The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high binding specificity. The example to emulated has been a heparin-derived pentasaccharide that binds to antithrombin-III with high affinity. However, the portability of this model to other biological situations is questioned on several accounts. Because of their structural flexibility, oligosaccharides with different sulfation and uronic acid conformation can display the same binding proficiency to different proteins and produce comparable biological effects. This circumstance represents a formidable obstacle to the design of drugs based on the heparin scaffold. The conceptual framework discussed in this article is that through a direct intervention on the heparin-binding functionality of proteins is possible to achieve a high degree of action specificity. This objective is currently pursued through two strategies. The first makes use of small molecules for which in the text we provide examples from past and present literature concerning angiogenic factors and enzymes. The second approach entails the mutagenesis of the GAG-binding site of proteins as a means to generate a new class of biologics of therapeutic interest. View Full-Text
Keywords: sulfated glycosaminoglycans; heparin-binding proteins; fibroblast growth factor; chemokines; xylosides; sulfotransferase inhibitors; heparanase; small molecule drugs sulfated glycosaminoglycans; heparin-binding proteins; fibroblast growth factor; chemokines; xylosides; sulfotransferase inhibitors; heparanase; small molecule drugs
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Ghiselli, G. Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends. Medicines 2019, 6, 80.

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