Hybrid Multivalent Jack Bean α-Mannosidase Inhibitors: The First Example of Gold Nanoparticles Decorated with Deoxynojirimycin Inhitopes.

Costanza Vanni,Camilla Matassini,Marco Marradi,Francesca Cardona,Sergio Moya,Andrea Goti,Philippe Compain,Anne Bodlenner,Maria De Los Angeles Ramirez,Jérémy P Schneider

doi:10.3390/molecules26195864

Abstract

Among carbohydrate-processing enzymes, Jack bean α-mannosidase (JBα-man) is the glycosidase with the best responsiveness to the multivalent presentation of iminosugar inhitopes. We report, in this work, the preparation of water dispersible gold nanoparticles simultaneously coated with the iminosugar deoxynojirimycin (DNJ) inhitope and simple monosaccharides (β-d-gluco- or α-d-mannosides). The display of DNJ at the gold surface has been modulated (i) by using an amphiphilic linker longer than the aliphatic chain used for the monosaccharides and (ii) by presenting the inhitope, not only in monomeric form, but also in a trimeric fashion through combination of a dendron approach with glyconanotechnology. The latter strategy resulted in a strong enhancement of the inhibitory activity towards JBα-man, with a Ki in the nanomolar range (Ki = 84 nM), i.e., more than three orders of magnitude higher than the monovalent reference compound.

Highlights

In this work, the preparation of water dispersible gold nanoparticles simultaneously coated with the iminosugar deoxynojirimycin (DNJ) inhitope and simple monosaccharides (β-D-glucoor α-D-mannosides)
More than ten years have passed since the first example of a trivalent deoxynojirimycin (DNJ) derivative, that displayed a small, but quantifiable, inhibitory multivalent effect for Jack bean α-mannosidase (JBα-man), was reported [1]
We report, in this work, the first example of gold nanoparticles decorated with the iminosugar deoxynojirimycin (DNJ)

Summary

Introduction

More than ten years have passed since the first example of a trivalent deoxynojirimycin (DNJ) derivative, that displayed a small, but quantifiable, inhibitory multivalent effect for Jack bean α-mannosidase (JBα-man), was reported [1]. The multivalency concept was considered an exclusive prerogative of lectin-carbohydrate interactions, and its application to carbohydrate-processing enzymes was almost completely unexplored, being considered extremely challenging, from a practical standpoint, and theoretically arguable. The refutation of such speculations was apparent in 2010, when a fullerene-based 12-valent DNJ compound showed binding enhancements towards JBα-man up to three orders of magnitude over the monovalent counterpart (inhibition constant Ki = 0.15 μM vs Ki = 188 μM) [2]. The outstanding multivalent effect observed with this 36-valent cluster has been fully rationalized thanks to the recent achievement of the first high resolution crystal structure of its complex with JBα-man [11]

Methods

Results

Conclusion