New Derivatives of L-Idonojirimycin Working As Pharmacological Chaperones for the Treatment of Gaucher Disease
Authors: Alfonso Pilar , Gervas Javier , Andreu Vanesa , Navascues Joaquin , Sanchez-Jimenez Francisca , Pocovi Miguel , Ortiz-Mellet Carmen , Garcia-Fernandez Jose M , Giraldo Pilar 
Published: October 2019

Abstract
Abstract 3270

Introduction:
Many of the mutations of the lysosomal acid b-glucosidase (b-glucocerebrosidase) associated with Gaucher disease (GD) translate into enzymes that retain partial catalytic activity in vitro but exhibit impaired cellular trafficking as a consequence of aberrant folding. Current investigational therapeutic strategies for include the development of ligands of the enzyme capable of promoting those conformational changes that are required for efficient folding, restoring trafficking. Although somewhat counter intuitive, competitive inhibitors of this b-glucocerebrosidase, at subinhibitory concentrations, can increase steady-state lysosomal levels of active enzyme through this rescuing mechanism, acting as “pharmacological chaperones”. At the massive lysosomal substrate concentration, the inhibitor would be replaced from the active site of the enzyme and the metabolic activity recovered. However, most of the pharmacological chaperones under study are iminosugars that behave as broad spectrum inhibitors, inhibiting simultaneously several glucosidases, which represents a serious inconvenient for clinical applications. An additional problem is that iminosugars and their derivatives are not active as pharmacological chaperones for glucocerebrosidase mutations located outside the domain containing the active site and are associated with neurological involvement, as the L444P mutation.

Aim:
The aim of this work is to present molecules with a high binding specificity towards b-glucocerebrosidase, with a high ratio of chaperone versus inhibitor activity and capable of producing an increased in the levels of mutant enzymes associated with Gaucher disease, including mutations located outside the catalytic domain.

Methods:
Different bicyclic derivatives of L-idonojirimycin were designed and chemically synthesized from D-glucose after in silico structural analysis and identification of the most favorable molecular features to interact with the active site of glucocerebrosidase. The chaperone potential of these compounds was evaluated at different concentrations in vitro using a cell model of GDcarrying the more frequent mutations in Gaucher disease, namely N370S and L444P. (P201230804).

Results:
The obtained results showed an increase in b-glucocerebrosidase activity at various chaperone concentrations, ranging from 1.96 to 4.98 folds for the L444P mutant and from 2.01 to 3.06 folds for the N370S mutation. Comments: The bicyclic derivatives of L-idonojirimycin could be considered as a therapeutic alternative for GD, mainly in patients with mutations located outside the active site of the enzyme and associated with neurologic involvement.

Disclosures:
Giraldo: Actelion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.