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bioRxiv · 10.1101/2025.03.02.641094

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

Kotlyar, M.·Guo, Z.·Rao, A. V. S.·Peng, H.·Wang, J.·Ma, Z.·Schiene-Fischer, C.·Fischer, G.·Liu, J. O.
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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. TOC GRAPHIC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/641094v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@d69b12org.highwire.dtl.DTLVardef@15ee120org.highwire.dtl.DTLVardef@e2495org.highwire.dtl.DTLVardef@83e270_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kotlyar, M., Guo, Z., Rao, A. V. S., Peng, H., Wang, J., Ma, Z., Schiene-Fischer, C., Fischer, G., Liu, J. O.. 2025-03-10. Identification of Rapaglutin E as An Isoform-specific Inhibitor of Glucose Transporter 1. https://doi.org/10.1101/2025.03.02.641094

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