1. Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor
- Author
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Alexander N. Lobov, Natalia L. Klyachko, Olga Y. Burenina, Ivan V Kislyakov, Yan A. Ivanenkov, Galina S Reshitko, Sergey V. Kovalev, Elena K. Beloglazkina, Irina V. Saltykova, Alexander Erofeev, Dmitry O Shkil, Emil Yu. Yamansarov, Elena V Lopatukhina, Peter Gorelkin, Anastasiia S Garanina, Olga A. Dontsova, Alexander G. Majouga, Sergei A Evteev, and Anton V Lopukhov
- Subjects
Tris ,Azides ,Protein Conformation ,In silico ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Galactosamine ,02 engineering and technology ,Asialoglycoprotein Receptor ,Chemistry Techniques, Synthetic ,Gene delivery ,Ligands ,01 natural sciences ,chemistry.chemical_compound ,Humans ,Surface plasmon resonance ,Pharmacology ,Esterification ,010405 organic chemistry ,Chemistry ,Ligand ,Organic Chemistry ,Hep G2 Cells ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,0104 chemical sciences ,Molecular Docking Simulation ,Alkynes ,Drug Design ,Drug delivery ,PC-3 Cells ,Hepatocytes ,Asialoglycoprotein receptor ,0210 nano-technology ,Methane ,Biotechnology ,Conjugate - Abstract
Since the asialoglycoprotein receptor (also known as the "Ashwell-Morell receptor" or ASGPR) was discovered as the first cellular mammalian lectin, numerous drug delivery systems have been developed and several gene delivery systems associated with multivalent ligands for liver disease targeting are undergoing clinical trials. The success of these systems has facilitated the further study of new ligands with comparable or higher affinity and less synthetic complexity. Herein, we designed two novel trivalent ligands based on the esterification of tris(hydroxymethyl) aminomethane (TRIS) followed by the azide-alkyne Huisgen cycloaddition with azido N-acetyl-d-galactosamine. The presented triazolyl glycoconjugates exhibited good binding to ASGPR, which was predicted using in silico molecular docking and assessed by a surface plasmon resonance (SPR) technique. Moreover, we demonstrated the low level of in vitro cytotoxicity, as well as the optimal spatial geometry and the required amphiphilic balance, for new, easily accessible ligands. The conjugate of a new ligand with Cy5 dye exhibited selective penetration into HepG2 cells in contrast to the ASGPR-negative PC3 cell line.
- Published
- 2020