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

Summary, in English

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: Ian Cumpstey; Emma Salomonsson; Anders Sundin; Hakon Leffler; Ulf Nilsson
• Department/s: Centre for Analysis and Synthesis; Division of Microbiology, Immunology and Glycobiology - MIG
• Publishing year: 2007
• Language: English
• Pages: 1389-1398
• Publication/Series: ChemBioChem
• Volume: 8
• Issue: 12
• Links: http://dx.doi.org/10.1002/cbic.200700040
• Document type: Journal article
• Publisher: John Wiley & Sons Inc.
• Topic: Microbiology in the medical area; Immunology in the medical area
• Keywords: inhibitors; galectin; cation-pi interaction; arenes; carbohydrates
• Status: Published
• ISBN/ISSN/Other: ISSN: 1439-4227