From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein-Templated Synthesis.
Alzheimer Disease
/ drug therapy
Amyloid Precursor Protein Secretases
/ antagonists & inhibitors
Amyloid beta-Peptides
/ antagonists & inhibitors
Aspartic Acid Endopeptidases
/ antagonists & inhibitors
Cell Line
Enzyme Inhibitors
/ chemical synthesis
Humans
Ligands
Molecular Structure
Neuroprotective Agents
/ chemical synthesis
Triazoles
/ chemical synthesis
Alzheimer's disease
BACE1
in situ click chemistry
multitarget directed ligands
protein kinase inhibitors
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
23 08 2021
23 08 2021
Historique:
revised:
24
06
2021
received:
10
05
2021
pubmed:
26
6
2021
medline:
4
11
2021
entrez:
25
6
2021
Statut:
ppublish
Résumé
Multitarget directed ligands (MTDLs) are arising as promising tools to tackle complex diseases. The main goal of this work is to create powerful modulating agents for neurodegenerative disorders. To achieve this aim, we have combined fragments that inhibit key protein kinases involved in the main pathomolecular pathways of Alzheimer's disease (AD) such as tau aggregation, neuroinflammation and decreased neurogenesis, whilst looking for a third action in beta-secretase (BACE1), responsible of β-amyloid production. We obtained well-balanced MTDLs with in vitro activity in three different relevant targets and efficacy in two cellular models of AD. Furthermore, computational studies confirmed how these compounds accommodate adequately into the long and rather narrow BACE1 catalytic site. Finally, we employed in situ click chemistry using BACE1 as protein template as a versatile synthetic tool that allowed us to obtain further MTDLs.
Identifiants
pubmed: 34169618
doi: 10.1002/anie.202106295
pmc: PMC8457121
doi:
Substances chimiques
Amyloid beta-Peptides
0
Enzyme Inhibitors
0
Ligands
0
Neuroprotective Agents
0
Triazoles
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
BACE1 protein, human
EC 3.4.23.46
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
19344-19354Informations de copyright
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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