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

Year: 2017

Authors: Mirabella S., D’Adamio G., Matassini C., Goti A., Delgado S., Gimeno A., Robina I., Moreno-Vargas AJ., Sestak S., Jimenez-Barbero J., Cardona F.

Autors Affiliation: Univ Firenze, Dipartimento Chim Ugo Schiff, Via Lastruccia 3-13, I-50019 Sesto Fiorentino, FI, Italy; Univ Seville, Dept Quim Organ, Fac Quim, C Prof Garcia Gonzalez 1, E-41012 Seville, Spain; Slovak Acad Sci, Inst Chem, Ctr Glyc, Dubravska Cesta 9, Bratislava 84538, Slovakia; CIC bioGUNE, Bizkaia Sci & Technol Pk,Bldg 801A, Derio 48160, Spain; Basque Fdn Sci, Ikerbasque, Maria Diaz de Haro 5, Bilbao 48005, Spain;‎ EHU UPV, Dept Organ Chem 2, Leioa 48040, Spain; CNR INO, Via N Carrara 1, Sesto Fiorentino, FI, Italy

Abstract: Novel pyrrolidine-based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean alpha-mannosidase and a Golgi alpha-mannosidase from Drosophila melanogaster, as well as a good selectivity with respect to a lysosomal alpha-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 alpha-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.

Journal/Review: CHEMISTRY-A EUROPEAN JOURNAL

Volume: 23 (58)      Pages from: 14585  to: 14596

KeyWords: enzymes; iminosugars; inhibitors; multivalency; pyrrolidine
DOI: 10.1002/chem.201703011

Citations: 21
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