Mechanistic Insight into the Binding of Multivalent Pyrrolidines to a-Mannosidases

Novel pyrrolidine-based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean a-mannosidase and a Golgi a-mannosidase from Drosophila melanogaster, as well as a good selectivity with respect to a lysosomal a-mannosidase, which is important for anticancer applications. STD NMR and molecular modeling studies supported a multivalent mechanism with specific interactions of the bioactive iminosugars with Jack bean a-mannosidase. TEM studies suggested a binding mode that involves the formation of aggregates, which result from the intermolecular crosslinked network of interactions between the multivalent inhibitors and two or more dimers of JBMan heterodimeric subunits.