Titre :

A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: toward a new profile of indirect ?-secretase inhibitors

Auteur(s) :

Gay, Marion [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Evrard, Caroline [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Descamps, Florian [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Carato, Pascal [Auteur]
CIC Poitiers – Centre d'investigation clinique de Poitiers [CIC 1402]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Renault, Nicolas [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Coevoet, Mathilde [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Eddarkaoui, Sabiha [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Baud, Catherine [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Larchanche, Paul-Emmanuel [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Buee, Luc [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
El Bakali, Jamal [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Vingtdeux, Valerie [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Sergeant, Nicolas [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Melnyk, Patricia [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172

Titre de la revue :

European Journal of Medicinal Chemistry

Nom court de la revue :

Eur J Med Chem

Numéro :

159

Pagination :

104-125

Date de publication :

2018-11-05

ISSN :

1768-3254

Mot(s)-clé(s) en anglais :

Lysosome
beta-secretase
BACE-1
Indirect inhibitor
Alzheimer's disease
Phenotypic
Amyloid precursor protein
Chloroquine
Autophagy

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid β peptides (Aβ) is central to Alzheimer's disease (AD) etiology. Aβ peptides are produced by sequential cleavage of APP ...
Lire la suite >Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid β peptides (Aβ) is central to Alzheimer's disease (AD) etiology. Aβ peptides are produced by sequential cleavage of APP by β-secretase (BACE-1) and γ-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Aβ peptide production. However, this effect is accompanied by an inhibition of lysosome-mediated degradation pathways. Following on from the promising activity of two series of APP metabolism modulators derived from CQ, we sought to develop new series of compounds that would retain the inhibitory effects on Aβ production without altering lysosome functions. Herein, we applied a ligand-based pharmacophore modeling approach coupled with de novo design that led to the discovery of a series of biaryl compounds. Structure-activity relationship studies revealed that minor modifications like replacing a piperidine moiety of compound 30 by a cyclohexyl (compound 31) allowed for the identification of compounds with the desired profile. Further studies have demonstrated that compounds 30 and 31 act through an indirect mechanism to inhibit β-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on Aβ peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect β-secretase inhibitors.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
• Lille Neurosciences & Cognition (LilNCog) - U 1172

Date de dépôt :

2024-01-30T10:27:29Z
2024-03-18T13:20:48Z