Journal Article

DZNE-2020-02973

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation.

Kroth, H. ; Ansaloni, A. ; Varisco, Y. ; Jan, A. ; Sreenivasachary, N. ; Rezaei-Ghaleh, N. ; Giriens, V. ; Lohmann, S. ; López-Deber, M. P. ; Adolfsson, O. ; Pihlgren, M. ; Paganetti, P. ; Froestl, W. ; Nagel-Steger, L. ; Willbold, D. ; Schrader, T. ; Zweckstetter, M.DZNE* ; Pfeifer, A. ; Lashuel, H. A. ; Muhs, A. (Corresponding author)

2012
Soc.60645 Bethesda, Md.

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Please use a persistent id in citations: doi:10.1074/jbc.M112.357665

Abstract: Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.

Keyword(s): Amyloid beta-Peptides: antagonists & inhibitors (MeSH) ; Amyloid beta-Peptides: chemistry (MeSH) ; Cell Line, Tumor (MeSH) ; Cytotoxins: antagonists & inhibitors (MeSH) ; Cytotoxins: chemistry (MeSH) ; Humans (MeSH) ; Hydrogen Bonding (MeSH) ; Hydrophobic and Hydrophilic Interactions (MeSH) ; Peptide Fragments: antagonists & inhibitors (MeSH) ; Peptide Fragments: chemistry (MeSH) ; Protein Structure, Secondary (MeSH) ; Pyrazoles: chemistry (MeSH) ; Structure-Activity Relationship (MeSH) ; 3-aminopyrazole ; Amyloid beta-Peptides ; Cytotoxins ; Peptide Fragments ; Pyrazoles ; amyloid beta-protein (1-42)

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Contributing Institute(s):

1. Structural Biology in Dementia (AG Zweckstetter)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2012

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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