Scaffold optimisation and activity evaluation of tetra-pseudoglycosylated MBL antagonists

Mannose Binding Lectin (MBL) is a circulating multimeric calcium dependent (C-lectin) protein that acts as a first-line host defence by selectively recognizing and binding to polyglycosylated surfaces of invading pathogens or damaged self cells.1MBL is also able to modulate inflammation and it is likely involved in reperfusion damage in acute stroke,2 therefore representing an attractive target for the development of new drugs against this disease. Our groups have already reported that pseudoglycosylated tetravalent dendrimers based on polyester scaffolds are good antagonists of MBL, with kd values in the low micromolar range. They were shown to supply a protective effect in a mouse model of brain stroke, reducing the reperfusion damage with a surprisingly wide therapeutic window.3 Unfortunately, these constructs proved to be rather chemically unstable: the polyester scaffold does not survive silica gel chromatography in either direct or reverse phase and slowly hydrolyses in water solution at physiological pH (27% hydrolysis in 6h). Here we present the synthesis of new dendrimers characterised by a stabilised version of the scaffold that allows to obtain still water soluble compounds with a grater chemical stability. Results of in vitro SPR binding assays of the new dendrimers to MBL will also be discussed.