Identification of Rapaglutin E as An Isoform-specific Inhibitor of Glucose Transporter 1

ABSTRACT Natural products rapamycin and FK506 are macrocyclic compounds with therapeutic benefits whose unique scaffold inspired the generation and exploration of the 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 recognition of GLUTs. Competing Interest Statement A patent application covering rapaglutin E and analogs has been filed by Johns Hopkins University and licensed to Rapafusyn Pharmaceuticals Inc., of which JOL is a board member and equity holder. The arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies.