Molecular basis for inhibiting human glucose transporters by exofacial inhibitors

Nan Wang, Shuo Zhang, Yafei Yuan, Hanwen Xu, Elisabeth Defossa, Hans Matter, Melissa Besenius, Volker Derdau, Matthias Dreyer, Nis Halland, Kaihui Hu He, Stefan Petry, Michael Podeschwa, Norbert Tennagels, Xin Jiang () and Nieng Yan ()
Additional contact information
Nan Wang: Tsinghua University
Shuo Zhang: Tsinghua University
Yafei Yuan: Tsinghua University
Hanwen Xu: Tsinghua University
Elisabeth Defossa: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Hans Matter: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Melissa Besenius: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Volker Derdau: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Matthias Dreyer: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Nis Halland: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Kaihui Hu He: Sanofi-Aventis Deutschland GmbH, R&D, CMC Synthetics Early Development Analytics
Stefan Petry: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Michael Podeschwa: Sanofi-Aventis Deutschland GmbH, R&D, Integrated Drug Discovery
Norbert Tennagels: DIU Exploratory Pathobiology
Xin Jiang: Tsinghua University
Nieng Yan: Tsinghua University

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Human glucose transporters (GLUTs) are responsible for cellular uptake of hexoses. Elevated expression of GLUTs, particularly GLUT1 and GLUT3, is required to fuel the hyperproliferation of cancer cells, making GLUT inhibitors potential anticancer therapeutics. Meanwhile, GLUT inhibitor-conjugated insulin is being explored to mitigate the hypoglycemia side effect of insulin therapy in type 1 diabetes. Reasoning that exofacial inhibitors of GLUT1/3 may be favored for therapeutic applications, we report here the engineering of a GLUT3 variant, designated GLUT3exo, that can be probed for screening and validating exofacial inhibitors. We identify an exofacial GLUT3 inhibitor SA47 and elucidate its mode of action by a 2.3 Å resolution crystal structure of SA47-bound GLUT3. Our studies serve as a framework for the discovery of GLUTs exofacial inhibitors for therapeutic development.

Date: 2022
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DOI: 10.1038/s41467-022-30326-3

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