Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer's Disease.
J Am Soc Mass Spectrom
; 30(1): 85-93, 2019 Jan.
Article
en En
| MEDLINE
| ID: mdl-29713966
ABSTRACT
Alzheimer's disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid ß-protein, particularly the 42-residue alloform (Aß42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Aß inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule's efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Aß42 dodecamer at both high (110) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Aß42, destabilizes preformed fibrils, and reverses Aß42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development. Graphical Abstract.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Pirrolidinas
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Diseño de Fármacos
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Modelos Moleculares
/
Péptidos beta-Amiloides
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Espectrometría de Movilidad Iónica
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Nitrilos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Am Soc Mass Spectrom
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos