Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR

Benjamin Philipp Joseph
,
Verena Weber
,
Lisa Knüpfer
,
Alejandro Giorgetti
,
Mercedes Alfonso-Prieto
ORCID logo ,
Sybille Krauß
* ,
Paolo Carloni
* ORCID logo ,
Giulia Rossetti
* ORCID logo
Version 1 : Received: 1 August 2023 / Approved: 2 August 2023 / Online: 3 August 2023 (10:11:15 CEST)

A peer-reviewed article of this Preprint also exists.

Joseph, B.P.; Weber, V.; Knüpfer, L.; Giorgetti, A.; Alfonso-Prieto, M.; Krauß, S.; Carloni, P.; Rossetti, G. Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR. Int. J. Mol. Sci. 2023, 24, 13127. Joseph, B.P.; Weber, V.; Knüpfer, L.; Giorgetti, A.; Alfonso-Prieto, M.; Krauß, S.; Carloni, P.; Rossetti, G. Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR. Int. J. Mol. Sci. 2023, 24, 13127.

Abstract

The RNA-binding protein Human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. The 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 chemoinformatics approaches, high throughput virtual screening and RNA–protein pull-down assays, we show that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits dose-dependent HuR inhibition in binding experiments. Importantly, the chemical scaffold is new with respect to the so-far known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein.

Keywords

RNA-binding protein; human antigen R (HuR); high-throughput virtual screening; small molecule inhibitors; RNA pulldown assay

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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