Kotlyar, M.; Guo, Z.; Rao, A. V. S.; Peng, H.; Wang, J.; Ma, Z.; Schiene-Fischer, C.; Fischer, G.; Liu, J. O.

Natural products rapamycin and FK506 are macrocyclic compounds with therapeu-tic benefits whose unique scaffold inspired the generation and exploration of the hy-brid macrocycle rapafucins. From this library, a potent inhibitor of the facilitative glu-cose 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 do-mains of RgE and RgA play key roles in recognition of GLUTs.