Synthesis of novel DC-SIGN ligands with an alpha-fucosylamide anchor.
The dendritic cell-specific intercellular adhesion molecule (ICAM) 3-grabbing nonintegrin (DC-SIGN) is a C-type lectin that appears to perform several different functions. Besides mediating adhesion between dendritic cells and T lymphocytes, DC-SIGN recognizes several pathogens some of which, including HIV, appear to exploit it to invade host organisms. The intriguing diversity of the roles attributed to DC-SIGN and their therapeutic implications have stimulated the search for new ligands that could be used as biological probes and possibly as lead compounds for drug development. The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. Using the known 3D structure of the Lewis-x trisaccharide, we have identified some monovalent alpha-fucosylamides that bind to DC-SIGN with inhibitory constants 0.4-0.5 mM, as determined by SPR, and have characterized their interaction with the protein by STD NMR spectroscopy. This work establishes for the first time alpha-fucosylamides as functional mimics of chemically and enzymatically unstable alpha-fucosides and describes interesting candidates for the preparation of multivalent systems able to block the receptor DC-SIGN with high affinity and with potential biomedical applications.
Timpano
Gabriele
G
Dipartimento di Chimica Organica e Industriale and CISI, Università di Milano, via Venezian 21, 20133 Milano, Italy.
Tabarani
Georges
G
Anderluh
Marko
M
Invernizzi
Donatella
D
Vasile
Francesca
F
Potenza
Donatella
D
Nieto
Pedro M
PM
Rojo
Javier
J
Fieschi
Franck
F
Bernardi
Anna
A
D000577:Amides / Q000737:chemistry; D000606:Amino Sugars / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005110:Extracellular Space / Q000378:metabolism; D005643:Fucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000577:Amides; D000606:Amino Sugars; D015815:Cell Adhesion Molecules; D005643:Fucose; D037181:Lectins, C-Type; D008024:Ligands; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin