A novel nonselective atypical PKC agonist could protect neuronal cell line from Aßoligomer induced toxicity by suppressing Aß generation.
Mol Med Rep
; 25(5)2022 May.
Article
em En
| MEDLINE
| ID: mdl-35244193
ABSTRACT
Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apicalbasal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer's disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selectionmass spectrometry, before in vitro kinase activity was used to determine the function of the hit compounds. A cellbased model assay that can mimic the pathology of AD was then established and used to assess the function of these hit compounds. As a result, the aPKC agonist Z640 was identified, which could bind to PKCι in silico, in vitro and in this cellbased model. Z640 was further confirmed as a nonselective aPKC agonist that can activate the kinase activity of both PKCι and PKCζ. In the cellbased assay, Z640 was found to protect neuronal cell lines from amyloidß (Aß) oligomerinduced cell death by reducing reactive oxygen species production and restore mitochondrial function. In addition, Z640 could reduce Aß40 generation in a dosedependent manner and shift amyloid precursor protein processing towards the nonamyloid pathway. To conclude, the present study is the first, to the best of the authors' knowledge to identify an aPKC agonist by combining computerassisted drug discovery and cellbased assays. The present study also revealed that aPKC agonists have therapeutic potential for the treatment of AD.
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01-internacional
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MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Isoenzimas
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2022
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Article