Supercharging Prions via Amyloid-Selective Lysine Acetylation.
Angew Chem Int Ed Engl
; 60(27): 15069-15079, 2021 06 25.
Article
em En
| MEDLINE
| ID: mdl-33876528
ABSTRACT
Repulsive electrostatic forces between prion-like proteins are a barrier against aggregation. In neuropharmacology, however, a prion's net charge (Z) is not a targeted parameter. Compounds that selectively boost prion Z remain unreported. Here, we synthesized compounds that amplified the negative charge of misfolded superoxide dismutase-1 (SOD1) by acetylating lysine-NH3+ in amyloid-SOD1, without acetylating native-SOD1. Compounds resembled a "ball and chain" mace a rigid amyloid-binding "handle" (benzothiazole, stilbene, or styrylpyridine); an aryl ester "ball"; and a triethylene glycol chain connecting ball to handle. At stoichiometric excess, compounds acetylated up to 9 of 11 lysine per misfolded subunit (ΔZfibril =-8100 per 103 subunits). Acetylated amyloid-SOD1 seeded aggregation more slowly than unacetylated amyloid-SOD1 in vitro and organotypic spinal cord (these effects were partially due to compound binding). Compounds exhibited reactivity with other amyloid and non-amyloid proteins (e.g., fibrillar α-synuclein was peracetylated; serum albumin was partially acetylated; carbonic anhydrase was largely unacetylated).
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Príons
/
Superóxido Dismutase-1
/
Amiloide
/
Lisina
Limite:
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos