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Studies of Arginine–Arene Interactions through Synthesis and Evaluation of a Series of Galectin‐Binding Aromatic Lactose Esters
Author(s) -
Cumpstey Ian,
Salomonsson Emma,
Sundin Anders,
Leffler Hakon,
Nilsson Ulf J.
Publication year - 2007
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700040
Subject(s) - chemistry , galectin , side chain , arginine , aromaticity , stereochemistry , aromatic amino acids , residue (chemistry) , intramolecular force , combinatorial chemistry , organic chemistry , biochemistry , molecule , amino acid , polymer
Aromatic lactose 2‐ O ‐esters were synthesized and used to probe arene–arginine interactions with the galectin family of proteins. They were found to be low μ M inhibitors of galectin‐1, ‐3, and ‐9N‐terminal domain and moderate inhibitors of galectin‐7, but not inhibitors of galectin‐8N‐terminal, which lacks an arginine residue close to the critical, esterified lactose 2‐ O ‐position. Molecular modeling of galectins in complex with aromatic lactose 2‐ O ‐esters, as well as binding studies with a galectin‐3 R186S mutant, confirmed that the inhibitory efficiency of the lactose 2‐ O ‐esters was due to the formation of strong interactions between the aromatic ester moieties and the arginine guanidinium groups of galectin‐1 and ‐3. An important common feature shared by galectin‐1 and ‐3 was that the arginines formed in‐plane ion pairs with two side‐chain carboxylates, which resulted in extended planar π‐electron surfaces that did not require solvation by water; these surfaces were ideal for stacking with aromatic moieties of the ligands. The results provide a basis for the design of lectin inhibitors and drugs that exploit interactions with arginine side‐chains via aromatic moieties, which are involved in intramolecular protein salt bridges.