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Studies of arginine-arene interactions through synthesis and evaluation of a series of galectin-binding aromatic lactose esters

Cumpstey, Ian LU ; Salomonsson, Emma LU ; Sundin, Anders LU ; Leffler, Hakon LU and Nilsson, Ulf LU (2007) In ChemBioChem 8(12). p.1389-1398
Abstract
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 mu m inhibitors of galectin-1, -3, and -9N-terminal domain and moderate inhibitors of galectin-7, but not inhibitors of galectin-8N-terminal, which locks 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... (More)
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 mu m inhibitors of galectin-1, -3, and -9N-terminal domain and moderate inhibitors of galectin-7, but not inhibitors of galectin-8N-terminal, which locks 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 pi-electron surfaces that did not require solvation by water; these surfaces were ideal for stocking 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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
inhibitors, galectin, cation-pi interaction, arenes, carbohydrates
in
ChemBioChem
volume
8
issue
12
pages
1389 - 1398
publisher
John Wiley & Sons
external identifiers
  • wos:000248851700011
  • scopus:34548118303
ISSN
1439-4227
DOI
10.1002/cbic.200700040
language
English
LU publication?
yes
id
c14e4450-6997-4f3a-ac55-92b0ecdad95d (old id 689584)
date added to LUP
2007-12-06 11:35:35
date last changed
2017-06-18 03:44:14
@article{c14e4450-6997-4f3a-ac55-92b0ecdad95d,
  abstract     = {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 mu m inhibitors of galectin-1, -3, and -9N-terminal domain and moderate inhibitors of galectin-7, but not inhibitors of galectin-8N-terminal, which locks 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 pi-electron surfaces that did not require solvation by water; these surfaces were ideal for stocking 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.},
  author       = {Cumpstey, Ian and Salomonsson, Emma and Sundin, Anders and Leffler, Hakon and Nilsson, Ulf},
  issn         = {1439-4227},
  keyword      = {inhibitors,galectin,cation-pi interaction,arenes,carbohydrates},
  language     = {eng},
  number       = {12},
  pages        = {1389--1398},
  publisher    = {John Wiley & Sons},
  series       = {ChemBioChem},
  title        = {Studies of arginine-arene interactions through synthesis and evaluation of a series of galectin-binding aromatic lactose esters},
  url          = {http://dx.doi.org/10.1002/cbic.200700040},
  volume       = {8},
  year         = {2007},
}