CuAAC AND IN SITU SCREENING FOR THE RAPID DISCOVERY OF DIVALENT GLYCOSIDASE INHIBITORS

摘要

Multivalent glycosidase inhibitors with extremely enhanced activity with respect to the monovalent parent, on a valence-corrected basis, have been successfully developed only for a-mannosidases [1] and, to a lesser extent, for hexosaminidases [2]. To achieve multivalency, the design of the adequate multimeric iminosugar by anchoring the monomeric inhitope to a functionalized platform through appropriate spacers is crucial. Concerning the search for divalent inhibitors, short and flexible spacers may favor the divalent effect through the so-called "recapture" mechanism. On the other hand, for the simultaneous interaction of both inhitopes with the enzyme, the nature and length of the spacer is critical to promote the right orientation of the binding motifs. Additionally, adventitious interactions of the spacer itself with the enzyme should not be discarded. As no structural information is available for many glycosidases, it is difficult to anticipate which spacer is the optimum. Thus, the development of a combinatorial methodology to explore the structure-activity relationships between different dimeric inhibitors and a particular glycosidase, could allow us to select the best spacer to maximize the divalent effect in glycosidase inhibition.