Tetravalent glycocyclopeptide with nanomolar affinity to wheat germ agglutinin.
A series of tetravalent glycocyclopeptides functionalized with GlcNAc was synthesized using copper(i)-catalysed alkyne-azide cycloaddition, oxime ligation and thiol-ene coupling. The binding ability of these compounds towards wheat germ agglutinin was studied by a competitive ELLA test and ITC experiments. While all compounds were able to inhibit WGA binding to GlcNAc-polymer coated surfaces at low concentrations, derivative 17 having an aliphatic spacer and thioether linkage was 4.9 × 10(6) times more potent on a per sugar basis than GlcNAc. This remarkably strong effect was confirmed by ITC experiments as these revealed an association constant of 9 nM for this compound, therefore presenting a gain of 200,000 times over GlcNAc. These results for compound 17 represent the highest binding properties reported for WGA.
Département de Chimie Moléculaire, UMR-CNRS 5250 & ICMG FR 2607, Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 9, France. olivier.renaudet@ujf-grenoble.fr.
Michele
M
Fiore
Nathalie
N
Berthet
Alberto
A
Marra
Emilie
E
Gillon
Pascal
P
Dumy
Alessandro
A
Dondoni
Anne
A
Imberty
Olivier
O
Renaudet
D000117:Acetylglucosamine / Q000737:chemistry; D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D001665:Binding Sites / Q000187:drug effects; D002151:Calorimetry; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014909:Wheat Germ Agglutinins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000480:Alkynes; D001386:Azides; D006020:Glycopeptides; D010456:Peptides, Cyclic; D011108:Polymers; D014909:Wheat Germ Agglutinins; D003300:Copper; D000117:Acetylglucosamine