2. Academic Validation
  3. Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD

Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD

  • Angew Chem Int Ed Engl. 2024 Mar 18;63(12):e202315997. doi: 10.1002/anie.202315997.
Junfei Cheng 1 2,  Jing Zhang 3,  Shipeng He 4,  Minyong Li 5,  Guoqiang Dong 1,  Chunquan Sheng 1
Affiliations

Affiliations

  • 1 Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai, 200433, China.
  • 2 Nautical Medicine Experimental Teaching Demonstration Center of Educational Institutions, Faculty of Naval Medicine, Second Military Medical University (Naval Medical University), Shanghai, 200433, China.
  • 3 Department of Pathology, Changzheng Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200433, China.
  • 4 Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
PMID: 38282119 DOI: 10.1002/anie.202315997
Abstract

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+ .

Keywords

NAD+; NAMPT; PROTAC; activator; photopharmacology; photoswitch.

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