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Design and in vitro analysis of SIRT2 inhibitor targeting Parkinson’s disease

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Abstract

Inhibition of Sirtuin2 (SIRT2) protein rescues the α-synuclein toxicity in vitro and in vivo models of Parkinson’s disease (PD). Thioacetyl group can structurally mimic the acetyl group and restrain the deacetylating p53 reaction by SIRT2. This work evaluated the biological activity of designed pentapeptides inhibitor containing N-thioacetyl-lysine against SIRT2. Pentapeptide by introducing thioacetyl-lysine as an inhibitor of SIRT2 was screened by molecular docking and synthesized by solid phase method. The inhibition of pure recombinant SIRT2 as well as SIRT2 in serum of PD patients by peptide was done by fluorescent activity assay. The inhibition of SIRT2 was assessed in PC12 cell line by measuring acetylated α-tubulin level. The peptide YKK(ε-thioAc)AM and HRK(ε-thioAc)AM were found to be SIRT2 inhibitors by molecular docking. However, YKK(ε-thioAc)AM was more specific towards SIRT2 than SIRT1 (Sirtuin1). It inhibited recombinant SIRT2 by IC50 value of 0.15 µM and KD values 9.92 × 10−8/M. It also inhibited serum SIRT2 of PD. It increased the acetylation of α-tubulin in PC12 neuroblastoma cells which is essential for maintaining the microtubular cell functions of brain. It can be concluded that novel peptide YKK(ε-thioAc)AM may be a platform for therapeutic agent for Parkinson’s disease targeting SIRT2.

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Acknowledgements

Authors acknowledge Council of Scientific and Industrial Research (CSIR) for providing funds for the consumable items.

Funding

Council of Scientific and Industrial Research (CSIR) (Grant No. 27(0335)/18/EMR-II) provided fund for the consumable items.

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Authors and Affiliations

  1. Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Amrendra Pratap Singh, Yudhishthir Yadav, Shashank Shekhar & Sharmistha Dey

  2. School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India

    Lokesh Nigam & Naidu Subbarao

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  1. Amrendra Pratap Singh
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  2. Lokesh Nigam
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  3. Yudhishthir Yadav
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  6. Sharmistha Dey
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Correspondence to Sharmistha Dey.

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Ethical approval was obtained from the All India Institute of Medical Sciences ethics committee (IEC-566/03 0.11.2017, RP-02/2017), New Delhi, India and written informed consent was recorded from the participants.

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Singh, A.P., Nigam, L., Yadav, Y. et al. Design and in vitro analysis of SIRT2 inhibitor targeting Parkinson’s disease. Mol Divers 25, 2261–2270 (2021). https://doi.org/10.1007/s11030-020-10116-z

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  • DOI: https://doi.org/10.1007/s11030-020-10116-z

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