1. Academic Validation
  2. Domain-Independent Inhibition of CBP/p300 Attenuates α-Synuclein Aggregation

Domain-Independent Inhibition of CBP/p300 Attenuates α-Synuclein Aggregation

  • ACS Chem Neurosci. 2021 Jul 7;12(13):2273-2279. doi: 10.1021/acschemneuro.1c00215.
Irena Hlushchuk 1 Heikki Ruskoaho 1 Andrii Domanskyi 2 Mikko Airavaara 1 3 Mika J Välimäki 1
Affiliations

Affiliations

  • 1 Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, Helsinki FI-00014, Finland.
  • 2 Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5 D, Helsinki FI-00014, Finland.
  • 3 Neuroscience Center, HiLIFE, University of Helsinki, Haartmaninkatu 8, Helsinki FI-00290, Finland.
Abstract

Neurodegenerative diseases are associated with failed proteostasis and accumulation of insoluble protein aggregates that compromise neuronal function and survival. In Parkinson's disease, a major pathological finding is Lewy bodies and neurites that are mainly composed of phosphorylated and aggregated α-synuclein and fragments of organelle membranes. Here, we analyzed a series of selective inhibitors acting on multidomain proteins CBP and p300 that contain both lysine acetyltransferase and bromodomains and are responsible for the recognition and enzymatic modification of lysine residues. By using high-affinity inhibitors, A-485, GNE-049, and SGC-CBP30, we explored the role of two closely related proteins, CBP and p300, as promising targets for selective attenuation of α-synuclein aggregation. Our data show that selective CBP/p300 inhibitors may alter the course of pathological α-synuclein accumulation in primary mouse embryonic dopaminergic neurons. Hence, drug-like CBP/p300 inhibitors provide an effective approach for the development of high-affinity drug candidates preventing α-synuclein aggregation via systemic administration.

Keywords

CBP; Parkinson’s disease; bromodomain; lysine acetyltransferase; p300; α-Synuclein.

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