Kinetic profiling of therapeutic strategies for inhibiting the formation of amyloid oligomers.
J Chem Phys
; 156(16): 164904, 2022 Apr 28.
Article
en En
| MEDLINE
| ID: mdl-35490011
Protein self-assembly into amyloid fibrils underlies several neurodegenerative conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that the small oligomers formed during this process constitute neurotoxic molecular species associated with amyloid aggregation. Targeting the formation of oligomers represents, therefore, a possible therapeutic avenue to combat these diseases. However, it remains challenging to establish which microscopic steps should be targeted to suppress most effectively the generation of oligomeric aggregates. Recently, we have developed a kinetic model of oligomer dynamics during amyloid aggregation. Here, we use this approach to derive explicit scaling relationships that reveal how key features of the time evolution of oligomers, including oligomer peak concentration and lifetime, are controlled by the different rate parameters. We discuss the therapeutic implications of our framework by predicting changes in oligomer concentrations when the rates of the individual microscopic events are varied. Our results identify the kinetic parameters that control most effectively the generation of oligomers, thus opening a new path for the systematic rational design of therapeutic strategies against amyloid-related diseases.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Neurodegenerativas
/
Amiloide
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Chem Phys
Año:
2022
Tipo del documento:
Article
País de afiliación:
Reino Unido
Pais de publicación:
Estados Unidos