Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease.
Eur J Med Chem
; 226: 113847, 2021 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-34555615
ABSTRACT
Transthyretin (TTR) has a well-established role in neuroprotection in Alzheimer's Disease (AD). We have setup a drug discovery program of small-molecule compounds that act as chaperones enhancing TTR/Amyloid-beta peptide (Aß) interactions. A combination of computational drug repurposing approaches and in vitro biological assays have resulted in a set of molecules which were then screened with our in-house validated high-throughput screening ternary test. A prioritized list of chaperones was obtained and corroborated with ITC studies. Small-molecule chaperones have been discovered, among them our lead compound Iododiflunisal (IDIF), a molecule in the discovery phase; one investigational drug (luteolin); and 3 marketed drugs (sulindac, olsalazine and flufenamic), which could be directly repurposed or repositioned for clinical use. Not all TTR tetramer stabilizers behave as chaperones in vitro. These chemically diverse chaperones will be used for validating TTR as a target in vivo, and to select one repurposed drug as a candidate to enter clinical trials as AD disease-modifying drug.
Palabras clave
AD disease-modifying drugs; Alzheimer's disease (AD); Alzheimer's disease drug discovery; Aß interaction; Computational screening; HTS screening; Multi-target screening; Protein-protein interactions; Repurposing; Small molecule chaperones (SMCs); Targeting transthyretin; Transthyretin; Transthyretin tetramer stability
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Prealbúmina
/
Chaperonas Moleculares
/
Bibliotecas de Moléculas Pequeñas
/
Descubrimiento de Drogas
/
Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
España