bc0c00202_si_001.pdf (2 MB)
Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor
journal contribution
posted on 2020-05-09, 16:04 authored by Galina
S. Reshitko, Emil Yu. Yamansarov, Sergei A. Evteev, Elena V. Lopatukhina, Dmitry O. Shkil’, Irina V. Saltykova, Anton V. Lopukhov, Sergey V. Kovalev, Alexander N. Lobov, Ivan V. Kislyakov, Olga Yu. Burenina, Natalia L. Klyachko, Anastasiia S. Garanina, Olga A. Dontsova, Yan A. Ivanenkov, Alexander S. Erofeev, Peter V. Gorelkin, Elena K. Beloglazkina, Alexander G. MajougaSince
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.
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New Trivalent LigandsHepatocyte TargetingAsialoglycoprotein ReceptorSPRCy 5 dyetriazolyl glycoconjugatesgene delivery systemsliver diseaseasialoglycoprotein receptorASGPR-negative PC 3 cell linenovel trivalent ligandsHepG 2 cellsazido NTRISsurface plasmon resonancedrug delivery systemsamphiphilic balance
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