Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD+

被引：7

作者：

Cheng, Junfei ^{[1
,2
]}

Zhang, Jing ^{[3
]}

He, Shipeng ^{[4
]}

Li, Minyong ^{[5
]}

Dong, Guoqiang ^{[1
]}

Sheng, Chunquan ^{[1
]}

机构：

[1] Second Mil Med Univ, Naval Med Univ, Ctr Basic Res & Innovat Med & Pharm MOE, Sch Pharm, Shanghai 200433, Peoples R China

[2] Second Mil Med Univ, Naval Med Univ, Naut Med Expt Teaching Demonstrat Ctr Educ Inst, Fac Naval Med, Shanghai 200433, Peoples R China

[3] Second Mil Med Univ, Naval Med Univ, Changzheng Hosp, Dept Pathol, Shanghai 200433, Peoples R China

[4] Shanghai Univ, Inst Translat Med, Shanghai 200444, Peoples R China

[5] Shandong Univ, Dept Med Chem, Key Lab Chem Biol MOE, Sch Pharmaceut Sci,Cheeloo Coll Med, Jinan 250012, Shandong, Peoples R China

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2024年 / 63卷 / 12期

基金：

中国国家自然科学基金;

关键词：

PROTAC; NAMPT; NAD(+); activator; photoswitch; photopharmacology; PROTEIN-DEGRADATION; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; METABOLISM;

D O I：

10.1002/anie.202315997

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Nicotinamide adenine dinucleotide (NAD(+)) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme involved in NAD(+) biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD(+) in biological systems using photoswitchable proteolysis-targeting chimeras (PS-PROTACs). An NAMPT activator and dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS-PROTACs, enabling up- and down-reversible regulation of NAMPT and NAD(+) in a light-dependent manner and reducing the toxicity associated with inhibitor-based PS-PROTACs. PS-PROTAC was activated under 620 nm irradiation, realizing in vivo optical manipulation of antitumor activity, NAMPT, and NAD(+).

引用

页数：13

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