A Set of Highly Sensitive Sirtuin Fluorescence Probes for Screening Small-Molecular Sirtuin Defatty-Acylase Inhibitors

被引：6

作者：

Nakajima, Yuya ^{[1
]}

Kawaguchi, Mitsuyasu ^{[1
]}

Ieda, Naoya ^{[1
]}

Nakagawa, Hidehiko ^{[1
]}

机构：

[1] Nagoya City Univ, Grad Sch Pharmaceut Sci, Nagoya, Aichi 4678603, Japan

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2021年 / 12卷 / 04期

关键词：

sirtuin; fluorescence probes; defatty-acylase activity; screening; inhibitors; PHYSIOLOGY; BIOLOGY; SWITCH;

D O I：

10.1021/acsmedchemlett.1c00010

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human sirtuins (SIRT1-7) regulate not only deacetylation but also deacylation of fatty acid-derived acyl moieties (defatty-acylation) at the epsilon-amino group of lysine residues. SIRT-subtype-specific defatty-acylase activity modulators are needed for detailed investigation of the biological roles of these enzymes, and to find suitable small molecules, we require appropriate screening systems. Here, we designed and synthesized a set of SIRT defatty-acylase activity probes with various quencher moieties and peptide sequences based on our previously developed one-step FRET-based SIRT probe SFP3, using improved methodology. Scanning of this set of probes with SIRT isozymes revealed that certain probe/isozyme combinations showed especially high responses. To illustrate the utility of the combinations thus identified, we applied compound 18/SIRT2 for inhibitor screening of a large chemical library. This enabled us to discover a new small molecule SIRT2-specific defatty-acylase inhibitor.

引用

页码：617 / 624

页数：8