selectivity over a large panel of commercially available glycosidases. Although a
significant decrease in affinity compared to the monovalent reference was observed on
sweet almond β-glucosidase, investigations on amyloglucosidase and bovine liver βglucosidase revealed no substantial improvements in using the multivalent approach.
More interestingly, better results emerged from the inhibition of green coffee αgalactosidase, Baker’s yeast isomaltase, and Penicillium decumbens naringinase
with inhibition constants of two orders of magnitude higher than that of the
corresponding monomer. The most spectacular result was obtained with the Jack
bean α-mannosidase, with a 180-fold enhancement in valency-corrected efficiency
of the globular dodecavalent conjugate 13 that compared very well with a previously
described trivalent congener [59].
These results unequivocally demonstrated the existence of tailored presentation
of peripheral recognition moieties insured by the rigid central scaffold. Clear
multivalent effects beyond the expected statistical rebinding and local concentration
effects was observed. In addition, the plausible implication of a sliding mechanism
of the inhibitors in the enzyme active site or an additional binding process at a close
allosteric site might explain the distinct specificity enhancement.
O
O
O
O
O
O
O
O
N
N
N
OH
HO
HO
OH
N
N
N
N
HO
HO
HO
OH
N
N
N
N
OH
HO
HO
OH
N
N
N
N
OH
OH
HO
HO
N
O
O
O
O
N
N
N
HO
HO
HO
OH
N
N N
N
HO
HO
HO
OH
N
O
O
O
O
N
N N
HO
OH
OH
HO
N
N
N
N
HOOH
OH
HO N
O
O
O
O
N
N N
OH
OH
OH
HO
N
N
N
N
OH
OH
OH
HO
N
O
O
O O
N
N
N
HO
HO
HO
OH
N
N
N
N
HO
HO
OH
HO N
13
Fig. 5 Dodecavalent fullereno-glycocluster with iminosugars as glycosidase inhibitors
308
N. Kottari et al.
significant decrease in affinity compared to the monovalent reference was observed on
sweet almond β-glucosidase, investigations on amyloglucosidase and bovine liver βglucosidase revealed no substantial improvements in using the multivalent approach.
More interestingly, better results emerged from the inhibition of green coffee αgalactosidase, Baker’s yeast isomaltase, and Penicillium decumbens naringinase
with inhibition constants of two orders of magnitude higher than that of the
corresponding monomer. The most spectacular result was obtained with the Jack
bean α-mannosidase, with a 180-fold enhancement in valency-corrected efficiency
of the globular dodecavalent conjugate 13 that compared very well with a previously
described trivalent congener [59].
These results unequivocally demonstrated the existence of tailored presentation
of peripheral recognition moieties insured by the rigid central scaffold. Clear
multivalent effects beyond the expected statistical rebinding and local concentration
effects was observed. In addition, the plausible implication of a sliding mechanism
of the inhibitors in the enzyme active site or an additional binding process at a close
allosteric site might explain the distinct specificity enhancement.
O
O
O
O
O
O
O
O
N
N
N
OH
HO
HO
OH
N
N
N
N
HO
HO
HO
OH
N
N
N
N
OH
HO
HO
OH
N
N
N
N
OH
OH
HO
HO
N
O
O
O
O
N
N
N
HO
HO
HO
OH
N
N N
N
HO
HO
HO
OH
N
O
O
O
O
N
N N
HO
OH
OH
HO
N
N
N
N
HOOH
OH
HO N
O
O
O
O
N
N N
OH
OH
OH
HO
N
N
N
N
OH
OH
OH
HO
N
O
O
O O
N
N
N
HO
HO
HO
OH
N
N
N
N
HO
HO
OH
HO N
13
Fig. 5 Dodecavalent fullereno-glycocluster with iminosugars as glycosidase inhibitors
308
N. Kottari et al.