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Mechanistic Insight into the Binding of Multivalent Pyrrolidines to α‐Mannosidases
Author(s) -
Mirabella Stefania,
D'Adamio Giampiero,
Matassini Camilla,
Goti Andrea,
Delgado Sandra,
Gimeno Ana,
Robina Inmaculada,
MorenoVargas Antonio J.,
Šesták Sergej,
JiménezBarbero Jesús,
Cardona Francesca
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201703011
Subject(s) - mannosidase , chemistry , pyrrolidine , golgi apparatus , stereochemistry , biochemistry , enzyme , endoplasmic reticulum
Novel pyrrolidine‐based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean α‐mannosidase and a Golgi α‐mannosidase from Drosophila melanogaster , as well as a good selectivity with respect to a lysosomal α‐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 α‐mannosidase. TEM studies suggested a binding mode that involves the formation of aggregates, which result from the intermolecular cross‐linked network of interactions between the multivalent inhibitors and two or more dimers of JBMan heterodimeric subunits.