Studies of arginine-arene interactions through synthesis and evaluation of a series of galectin-binding aromatic lactose esters.
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 microM 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 pi-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.
Cumpstey
Ian
I
Organic Chemistry, Lund University, P.O. Box 124, Lund, Sweden.
Salomonsson
Emma
E
Sundin
Anders
A
Leffler
Hakon
H
Nilsson
Ulf J
UJ
D001120:Arginine / Q000378:metabolism; D004952:Esters; D037483:Galectin 1; D037502:Galectin 3; D037161:Galectins / Q000737:chemistry; D007785:Lactose
D004952:Esters; D037483:Galectin 1; D037502:Galectin 3; D037161:Galectins; D001120:Arginine; D007785:Lactose