Cyclic peptide-based potent and selective SIRT1/2 dual inhibitors harboring Nε-thioacetyl-lysine

Di Chen; Weiping Zheng

doi:10.1016/j.bmcl.2016.09.055

Cyclic peptide-based potent and selective SIRT1/2 dual inhibitors harboring N^ε-thioacetyl-lysine

Bioorg Med Chem Lett. 2016 Nov 1;26(21):5234-5239. doi: 10.1016/j.bmcl.2016.09.055. Epub 2016 Sep 22.

Authors

Di Chen¹, Weiping Zheng²

Affiliations

¹ School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China.
² School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address: wzheng@ujs.edu.cn.

PMID: 27707605
DOI: 10.1016/j.bmcl.2016.09.055

Abstract

In the current study, we discovered that several N-terminus-to-side chain cyclic tripeptides harboring the catalytic mechanism-based SIRT1/2/3 inhibitory warhead N^ε-thioacetyl-lysine at their central positions exhibited a comparably strong inhibition (nM level) against the SIRT1/2-catalyzed N^ε-acetyl-lysine deacetylation reactions. Their dual SIRT1/2 inhibitory action was also found to be stronger than that against SIRT3/5/6. Considering the previous demonstration that a SIRT1/2 dual inhibition could be instrumental in achieving an anti-cancer effect on those cancers retaining the wild-type tumor suppresser p53 protein, these compounds could be employed as leads for developing novel anti-cancer agents.

Keywords: Cyclic peptide; Inhibitor; N(ε)-thioacetyl-lysine; SIRT1/2 dual inhibition; Sirtuin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Humans
Lysine / analogs & derivatives*
Lysine / chemistry
Lysine / pharmacology
Peptides, Cyclic / pharmacology*
Sirtuin 1 / antagonists & inhibitors*
Sirtuin 2 / antagonists & inhibitors*

Substances

N(epsilon)-thioacetyllysine
Peptides, Cyclic
SIRT1 protein, human
SIRT2 protein, human
Sirtuin 1
Sirtuin 2
Lysine