Mechanistic Insight into the Binding of Multivalent Pyrrolidines to α‐Mannosidases

• Published in: Chemistry : a European journal Vol. 23; no. 58; pp. 14585 - 14596
• Main Authors: Mirabella, Stefania, D'Adamio, Giampiero, Matassini, Camilla, Goti, Andrea, Delgado, Sandra, Gimeno, Ana, Robina, Inmaculada, Moreno‐Vargas, Antonio J., Šesták, Sergej, Jiménez‐Barbero, Jesús, Cardona, Francesca
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 17.10.2017
• Subjects: alpha-Mannosidase - antagonists & inhibitors; alpha-Mannosidase - genetics; alpha-Mannosidase - metabolism; Animals; Binding Sites; Catalytic Domain; Chemistry; Chemistry, Multidisciplinary; Drosophila melanogaster - enzymology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; enzymes; Humans; Imino Sugars - chemical synthesis; Imino Sugars - chemistry; Imino Sugars - metabolism; iminosugars; inhibitors; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Microscopy, Electron, Transmission; Molecular Dynamics Simulation; multivalency; Physical Sciences; Protein Structure, Tertiary; pyrrolidine; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Science & Technology; inhibitors; BETA-GLUCOCEREBROSIDASE; pyrrolidine; PHARMACOLOGICAL CHAPERONES; enzymes; TERMINAL ALKYNES; multivalency; GAUCHER-DISEASE; iminosugars; GLYCOSIDASE INHIBITION; HYACINTHACINE A; LIGANDS; STD-NMR SPECTROSCOPY; DERIVATIVES
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201703011

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. Multivalent glycosidase inhibitors: Synthesis, biological evaluation, NMR analysis, and molecular modeling studies underlines, for the first time, the existence of a specific interaction between the jack bean α‐mannosidase and pyrrolidine‐based multivalent inhibitors. TEM studies suggest the formation of an intermolecular cross‐linking network between enzyme and inhibitors.