Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
Mol Divers. 2021 Nov;25(4):2261-2270. doi: 10.1007/s11030-020-10116-z. Epub 2020 Jun 26.
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 IC value of 0.15 µM and KD values 9.92 × 10/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.
Sirtuin2（SIRT2）蛋白抑制剂可挽救帕金森病（PD）的体外和体内α-突触核蛋白毒性模型。硫代乙酰基可以结构模拟乙酰基并通过 SIRT2 抑制 p53 的去乙酰化反应。这项工作评估了含有 N-硫代乙酰基-赖氨酸的设计五肽抑制剂对 SIRT2 的生物学活性。通过将硫代乙酰基-赖氨酸作为 SIRT2 的抑制剂引入五肽，通过分子对接进行筛选，并通过固相法合成。通过荧光活性测定来测定肽对纯重组 SIRT2 以及 PD 患者血清中 SIRT2 的抑制作用。通过测量乙酰化α-微管蛋白水平来评估 PC12 细胞系中的 SIRT2 抑制作用。肽 YKK（ε-thioAc）AM 和 HRK（ε-thioAc）AM 通过分子对接被发现是 SIRT2 抑制剂。然而，YKK（ε-thioAc）AM 比 SIRT1（Sirtuin1）更特异于 SIRT2。它以 0.15μM 的 IC 值抑制重组 SIRT2，KD 值为 9.92×10/M。它还抑制 PD 患者的血清 SIRT2。它增加了 PC12 神经母细胞瘤细胞中α-微管蛋白的乙酰化，这对于维持大脑的微管细胞功能至关重要。可以得出结论，新型肽 YKK（ε-thioAc）AM 可能成为针对 SIRT2 的帕金森病治疗剂的平台。
