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Structural features of synthetic glycoconjugates and efficiency of their interaction with glycoprotein receptors on the surface of hepatocytes

https://doi.org/10.32362/2410-6593-2019-14-5-7-20

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Abstract

Objectives. Over the last few years, medicinal chemistry research has been focusing on the creation of molecules that can target particular body systems, organs and tissues, thus abating systemic toxicity and side effects, and, most of all, boosting therapeutic potential. This goal can be achieved through the specific interaction of such drugs with active sites of cellular receptors. For example, glycoprotein receptors that can be found on cellular surfaces in neural tissues and liver parenchyma, selectively bind various glycoproteins and glycosides, facilitating their penetration into cells. This review describes how certain parameters of ligand structure (the nature and length of the spacer between carbohydrate and non-carbohydrate fragments of the molecule, number of carbohydrate residues per molecule, etc.) influence the penetration efficiency of synthetic glycoconjugates into liver cells.

Methods. This review article summarizes 75 research papers and discusses data from in vitro and in vivo experiments showing which structures of synthetic carbohydrate derivatives are optimal for targeted drug delivery into liver cells.

Results. The surface of liver cells (hepatocytes) contains a significant number of asialoglycoprotein receptors (ASGP-R) that are almost never found elsewhere. This makes ASGP-R an ideal target for the directed treatment of liver diseases, including such difficult, socially important conditions as hepatocellular carcinoma and Hepatitis C. A number of various ligands and targeted (to ASGP-R) delivery systems have been designed. Such molecules always contain derivatives of mono- and disaccharides, most commonly D-glucose, D-galactose, D-lactose and N-acetylglucosamines. This review contains the chemical structures of carbohydrate-based ligands.

Conclusions. Glycolipids based on D-carbohydrates, when in liposomes, facilitate penetration into liver cells by a receptor-mediated, clathrin-dependent endocytosis mechanism that is activated upon contact of the carbohydrate-containing ligand fragment with the active site of ASGP-R. It can be addressed by the use of monovalent derivatives of carbohydrates as well as polyvalent glycoconjugates. Alterations in the ligand structure and the number of liposomal modifications can boost the therapeutic effect. The distance between the liposomal surface and the carbohydrate residue (spacer length), as well as the hydrophilic-lipophilic balance of the ligand molecule, have a great effect on the affinity and cellular response.

About the Authors

A. S. Nosova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Anastasiya S. Nosova, Master of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

86, Vernadskogo pr., Moscow, 119571, Russia


Competing Interests: The authors declare no conflict of interest.


Yu. A. Budanova
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Ulyana A. Budanova, Cand. of Sci. (Chemistry), Assistant of Professor of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

Scopus Author ID 14622352500, ResearcherID E-1659-2014

86, Vernadskogo pr., Moscow, 119571, Russia


Competing Interests: The authors declare no conflict of interest.


Yu. L. Sebyakin
MIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)
Russian Federation

Yury L. Sebyakin, Dr. of Sci. (Chemistry), Professor, Professor of the N.A. Preobrazhensky Chair of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry

Scopus Author ID 6701455145, ResearcherID T-2835-2019

86, Vernadskogo pr., Moscow, 119571, Russia


Competing Interests: The authors declare no conflict of interest.


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Supplementary files

1. Fig. 1. Schematic depiction of ASGP-R that showing a heterooligomer made up of two H1 subunits and one H2 subunit. The figure shows the spatial arrangement of the receptor’s binding sites [19].
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Nosova A.S., Budanova Yu.A., Sebyakin Yu.L. Structural features of synthetic glycoconjugates and efficiency of their interaction with glycoprotein receptors on the surface of hepatocytes. Fine Chemical Technologies. 2019;14(5):7-20. https://doi.org/10.32362/2410-6593-2019-14-5-7-20

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