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Eur J Med Chem. 2017 Feb 15;127:909-916. doi: 10.1016/j.ejmech.2016.11.001. Epub 2016 Nov 3.

Design, synthesis of allosteric peptide activator for human SIRT1 and its biological evaluation in cellular model of Alzheimer's disease.

Author information

1
Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
2
School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
3
Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India. Electronic address: sharmistha_d@hotmail.com.

Abstract

Sirtuin 1 (SIRT1) is one of the member of the mammalian proteins of the Sirtuin family of NAD+ dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid protein precursor (APP) in in-vitro cell culture studies and transgenic mouse models of Alzheimer's disease (AD). SIRT1 has been shown to have a protective role against (AD). It has been reported earlier that increasing SIRT1 activity can prevent AD in mice model. Tripeptide as an activator of SIRT1 were screened on the basis of structural information by molecular docking and synthesized by solid phase method. The enhancement of biochemical activity of pure recombinant SIRT1 as well as SIRT1 in serum of AD patients in presence of tripeptide was done by Fluorescent Activity Assay. The activity of SIRT1 by peptide was assessed in IMR-32 cell line by measuring acetylated p53 level. Further the protective effect of SIRT1 activator in cellular model of AD was analyzed by MTT assay. We find CWR tripeptide as a SIRT1 activator by molecular docking, enhanced the activity of SIRT1 protein by lowering the Michaelis constant, Km by allosteric mechanism. The activity of serum SIRT1 of AD was also increases by CWR. It also decreased the acetylation of p53 in IMR32 neuroblastoma cells and protected the cell death caused by Aβ amyloid fragments in cell line model of AD. Thus, it can be concluded that CWR may serve as platform to elucidate further small molecule activator as a therapeutic agent for AD targeting SIRT1.

KEYWORDS:

Activator; Allosteric; Aβ(25–35); IMR-32; Peptide; Sirtuin

PMID:
27836195
DOI:
10.1016/j.ejmech.2016.11.001
[Indexed for MEDLINE]

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