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

Year: 2025
Type: article
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.
DOI: 10.1021/acschembio.5c00152
Authors: Marnie Kotlyar, Zufeng Guo, A. V. Subba Rao, Hanjing Peng, Jingxin Wang, Zhongnan Ma, Cordelia Schiene-Fischer, Gunter Fischer, Jun O. Liu
Language: English
Open Access status: green
Awards: G1165598027, G3343527953, G4320405728, Acquisition of a 500 MHz NMR Spectrometer to Support Small-Molecule Chemistry at Johns Hopkins Medical School, G6233739917, G6775538508, The Chemistry-Biology Interface Program at Johns Hopkins University
OpenAlex ID: W4409432799
FWCI: 0.505
Cites: 35
Cited by: 2
Related to: 10