TY - JOUR
T1 - Scaffold Optimisation of Tetravalent Antagonists of the Mannose Binding Lectin
AU - Goti, Giulio
AU - Palmioli, Alessandro
AU - Stravalaci, Matteo
AU - Sattin, Sara
AU - De Simoni, Maria Grazia
AU - Gobbi, Marco
AU - Bernardi, Anna
PY - 2016/3/7
Y1 - 2016/3/7
N2 - Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C.
AB - Antagonists of mannose binding lectin (MBL) have shown a protective role against brain reperfusion damage after acute ischemic stroke. Here we describe the design and streamlined synthesis of glycomimetic MBL antagonists based on a new tetravalent dendron scaffold. The dendron was developed by optimisation of a known polyester structure previously demonstrated to be very efficient for ligand presentation to MBL. Replacement of a labile succinyl ester bond with a more robust amide functionality, use of a longer and more hydrophilic linker, fast modular synthesis and orthogonal functionalisation at the focal point are the main features of the new scaffold. The glycoconjugate constructs become stable to silica gel chromatography and to water solutions at physiological pH, while preserving water solubility and activity in an SPR assay against the murine MBL-C isoform. Higher-order constructs were easily assembled, as demonstrated by the synthesis of a 16-valent dendrimer, which leads to two orders of magnitude increase in activity over the tetravalent version against MBL-C.
KW - glycodendrimers
KW - glycomimetics
KW - mannose binding lectin
KW - multivalency
KW - surface plasmon resonance
UR - http://www.scopus.com/inward/record.url?scp=84979097791&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979097791&partnerID=8YFLogxK
U2 - 10.1002/chem.201504388
DO - 10.1002/chem.201504388
M3 - Article
C2 - 26696414
AN - SCOPUS:84954438470
VL - 22
SP - 3686
EP - 3691
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 11
ER -