Supercharging Prions via Amyloid-Selective Lysine Acetylation.

Autor: Baumer KM; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Cook CD; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Zahler CT; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Beard AA; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Chen Z; Department of Neuroscience, University of Florida, Gainesville, FL, USA., Koone JC; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Dashnaw CM; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Villacob RA; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Solouki T; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Wood JL; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Borchelt DR; Department of Neuroscience, University of Florida, Gainesville, FL, USA., Shaw BF; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2021 Jun 25; Vol. 60 (27), pp. 15069-15079. Date of Electronic Publication: 2021 May 26.
DOI: 10.1002/anie.202103548
Abstrakt: 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-NH 3 + 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 (ΔZ fibril =-8100 per 10 3 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).
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
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