2. Academic Validation
  3. Identification of Rapaglutin E as an Isoform-Specific Inhibitor of Glucose Transporter 1

Identification of Rapaglutin E as an Isoform-Specific Inhibitor of Glucose Transporter 1

  • ACS Chem Biol. 2025 May 16;20(5):1004-1009. doi: 10.1021/acschembio.5c00152.
Marnie Kotlyar 1 2 3,  Zufeng Guo 2 3,  A V Subba Rao 2 3,  Hanjing Peng 2 3,  Jingxin Wang 2 3,  Zhongnan Ma 2 3,  Cordelia Schiene-Fischer 4,  Gunter Fischer 5,  Jun O Liu 1 3 6
Affiliations

Affiliations

  • 1 Chemistry Biology Interface Graduate Program, Johns Hopkins University, Baltimore, Maryland 21218, United States.
  • 2 Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
  • 3 The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
  • 4 Department of Enzymology, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
  • 5 Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany.
  • 6 Departments of Pharmacology and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
PMID: 40226990 DOI: 10.1021/acschembio.5c00152
Abstract

Natural products rapamycin and FK506 are macrocyclic compounds with therapeutic benefits whose unique scaffold inspired the generation and exploration of hybrid macrocycle rapafucins. From this library, a potent inhibitor of the facilitative glucose transporter (GLUT), rapaglutin A (RgA), was previously identified. RgA is a pan-GLUT inhibitor of Class I isoforms GLUT1, GLUT3, and GLUT4. Herein, we report the discovery of rapaglutin E (RgE). Unlike RgA, RgE is highly specific for GLUT1. Further characterization revealed that RgE and RgA likely bound to distinct sites on GLUT1 despite their shared FKBP-binding domain, suggesting that the distinct effector domains of RgE and RgA play key roles in the recognition of GLUTs.

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