Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR

International Journal of Molecular Sciences, vol. 24, pp. 13127

Abstract

The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here, we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatic approaches, high-throughput virtual screening, and RNA-protein pulldown assays, we demonstrate that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits a dose-dependent HuR inhibition effect in binding experiments. Importantly, the chemical scaffold is new with respect to the currently known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.

Authors 8

1. Benjamin Philipp Joseph Aachen Faculty of Mathematics, Computer Science and Natural Sciences

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University, 52062 Aachen, Germany

   Institute for Neuroscience and Medicine and Institute for Advanced Simulations (INM-9/IAS-5), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany

2. Verena Weber Aachen Faculty of Mathematics, Computer Science and Natural Sciences

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University, 52062 Aachen, Germany

   Institute for Neuroscience and Medicine and Institute for Advanced Simulations (INM-9/IAS-5), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany

3. Lisa Knüpfer

   University of Siegen

   Affiliation as printed

   Institute of Biology, University of Siegen, 57076 Siegen, Germany

4. Alejandro Giorgetti

   Forschungszentrum Jülich · University of Verona

   Affiliation as printed

   Department of Biotechnology, University of Verona, 37134 Verona, Italy

   Institute for Neuroscience and Medicine and Institute for Advanced Simulations (INM-9/IAS-5), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany

5. Mercedes Alfonso‐Prieto

   Forschungszentrum Jülich

   Affiliation as printed

   Institute for Neuroscience and Medicine and Institute for Advanced Simulations (INM-9/IAS-5), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany

6. Sybille Krauß corresponding

   University of Siegen

   Affiliation as printed

   Institute of Biology, University of Siegen, 57076 Siegen, Germany

7. Paolo Carloni corresponding Aachen Faculty of Mathematics, Computer Science and Natural Sciences

   RWTH Aachen University · Forschungszentrum Jülich

   Affiliation as printed

   Faculty of Mathematics, Computer Science and Natural Sciences, RWTH Aachen University, 52062 Aachen, Germany

   Institute for Neuroscience and Medicine and Institute for Advanced Simulations (INM-9/IAS-5), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany

8. Giulia Rossetti Aachen Department of Neurology

   RWTH Aachen University · Forschungszentrum Jülich · Jülich Supercomputing Centre

   Affiliation as printed

   Department of Neurology, RWTH Aachen University, 44517 Aachen, Germany

   Institute for Neuroscience and Medicine and Institute for Advanced Simulations (INM-9/IAS-5), Computational Biomedicine, Forschungszentrum Jülich, 52425 Jülich, Germany

   Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, 52425 Jülich, Germany