Alpha-O-linked glycopeptide mimetics: synthesis, conformation analysis, and interactions with viscumin, a galactoside-binding model lectin.
Efficient cycloaddition of a silylidene-protected galactal with a suitable heterodiene yielded the basis for a facile diastereoselective route to a glycopeptide-mimetic scaffold. Its carbohydrate part was further extended by beta1-3-linked galactosylation. The pyranose rings retain their (4)C(1) chair conformation, as shown by molecular modeling and NMR spectroscopy, and the typical exo-anomeric geometry was observed for the disaccharide. The expected bioactivity was ascertained by saturation-transfer-difference NMR spectroscopy by using the galactoside-specific plant toxin viscumin as a model lectin. The experimental part was complemented by molecular docking. The described synthetic route and the strategic combination of computational and experimental techniques to reveal conformational properties and bioactivity establish the prepared alpha-O-linked glycopeptide mimetics as promising candidates for further exploitation of this scaffold to give O-glycans for lectin blocking and vaccination.
Jiménez-Barbero
Jesús
J
Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain. jjbarbero@cib.csic.es
Dragoni
Elisa
E
Venturi
Chiara
C
Nannucci
Federico
F
Ardá
Ana
A
Fontanella
Marco
M
André
Sabine
S
Cañada
Francisco Javier
FJ
Gabius
Hans-Joachim
HJ
Nativi
Cristina
C
D015195:Drug Design; D006020:Glycopeptides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D054790:Ribosome Inactivating Proteins, Type 2 / Q000737:chemistry* / Q000302:isolation & purification; D013237:Stereoisomerism; D014118:Toxins, Biological / Q000737:chemistry* / Q000302:isolation & purification
D006020:Glycopeptides; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; C488862:mistletoe lectin I