2. Academic Validation
  3. Rational design and evaluation of 2-((pyrrol-2-yl)methylene)thiophen-4-ones as RNase L inhibitors

Rational design and evaluation of 2-((pyrrol-2-yl)methylene)thiophen-4-ones as RNase L inhibitors

  • Eur J Med Chem. 2023 Aug 5;256:115439. doi: 10.1016/j.ejmech.2023.115439.
Jimin Hwang 1,  Neele Haacke 1,  Lydia Borgelt 1,  Xiaqiu Qiu 1,  Raphael Gasper 2,  Peng Wu 3
Affiliations

Affiliations

  • 1 Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, 44227, Germany.
  • 2 Crystallography and Biophysics Unit, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.
  • 3 Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany; Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany. Electronic address: peng.wu@mpi-dortmund.mpg.de.
PMID: 37201427 DOI: 10.1016/j.ejmech.2023.115439
Abstract

Ribonuclease L (RNase L) plays a crucial role in an Antiviral pathway of interferon-induced innate immunity by degrading RNAs to prevent viral replication. Modulating RNase L activity thus mediates the innate immune responses and inflammation. Although a few small molecule-based RNase L modulators have been reported, only limited molecules have been mechanistically investigated. This study explored the strategy of RNase L targeting by using a structure-based rational design approach and evaluated the RNase L-binding and inhibitory activities of the yielded 2-((pyrrol-2-yl)methylene)thiophen-4-ones, which exhibited improved inhibitory effect as determined by in vitro FRET and gel-based RNA cleavage assay. A further structural optimization study yielded selected thiophenones that showed >30-fold more potent inhibitory activity than that of sunitinib, the approved kinase inhibitor with reported RNase L inhibitory activity. The binding mode with RNase L for the resulting thiophenones was analyzed by using docking analysis. Furthermore, the obtained 2-((pyrrol-2-yl)methylene)thiophen-4-ones exhibited efficient inhibition of RNA degradation in cellular rRNA cleavage assay. The newly designed thiophenones are the most potent synthetic RNase L inhibitors reported to date and the results revealed in our study lay the foundation for the development of future RNase L-modulating small molecules with new scaffold and improved potency.

Keywords

Nucleotide mimetic; RNA cleavage; RNA degradation; RNase L inhibition; Small-molecule inhibitor.

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