Discovery and structure activity relationship of small molecule inhibitors of toxic ß-amyloid-42 fibril formation.
J Biol Chem
; 287(41): 34786-800, 2012 Oct 05.
Article
en En
| MEDLINE
| ID: mdl-22891248
ABSTRACT
Increasing evidence implicates Aß peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aß aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aß42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the ß-sheet conformation of Aß42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aß42. The efficacy of these compounds on inhibiting Aß fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aß42 leading to decreased cell toxicity.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Pirazoles
/
Péptidos beta-Amiloides
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2012
Tipo del documento:
Article
País de afiliación:
Suiza