Amylovis-201 is a new dual-target ligand,acting as an anti-amyloidogenic compound and a potent agonist of the σ_(1) chaperone protein  

作　　者：Laura Garcia-Pupo Lucie Crouzier Alberto Bencomo-Martinez Johann Meunier Axelle Morilleau Benjamin Delprat Marquiza Sablon Carrazana Roberto Menendez Soto del Valle Tangui Maurice Chryslaine Rodriguez-Tanty 

机构地区：[1]Department of Neurochemistry,Cuban Center for Neurosciences,Cubanacan,Playa,Havana CP 11600,Cuba [2]MMDN,University of Montpellier,EPHE,INSERM,Montpellier 34095,France [3]Laboratory of Protein Science,Proteomics and Epigenetic Signaling(PPES),Department of Biomedical Sciences,University of Antwerp,2610 Wilrijk,Belgium

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4345-4359,共15页药学学报（英文版）

基　　金：supported by a PHC Carlos J.Finlay program from Campus France(project 47069SA)to TM and CRT.

摘　　要：The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to form thermodynamically stable complexes with Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.

关 键 词：Alzheimer’s disease Amyloid-b aggregation Neuroprotection s1 receptor Drug discovery Molecular modelisation Zebrafish model Learning and memory 

分 类 号：R730.5[医药卫生—肿瘤]