Discovery of Small Molecule Drugs Targeting the Biogenesis of microRNA-155 for the Treatment of Systemic Lupus Erythematosus

Authors

  • Kamal Azzaoui Saverna Therapeutics AG, Pumpmattenweg 3 CH-4105 Biel-Benken, Switzerland;, Email: k.azzaoui@saverna.com
  • Marcel Blommers Saverna Therapeutics AG, Pumpmattenweg 3 CH-4105 Biel-Benken, Switzerland
  • Marjo Götte Saverna Therapeutics AG, Pumpmattenweg 3 CH-4105 Biel-Benken, Switzerland
  • Kaspar Zimmermann Saverna Therapeutics AG, Pumpmattenweg 3 CH-4105 Biel-Benken, Switzerland
  • He Liu Saverna Therapeutics AG, Pumpmattenweg 3 CH-4105 Biel-Benken, Switzerland
  • Heinz Fretz Saverna Therapeutics AG, Pumpmattenweg 3 CH-4105 Biel-Benken, Switzerland

DOI:

https://doi.org/10.2533/chimia.2020.798

Keywords:

Fbs, Machine learning, Microrna, Nmr, Sle

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that often leads to functional disorder in multiple organs, most often with symptoms related to skin lesions, cardiovascular disease and kidney damage. Although significant efforts have been made to find efficient therapies, it still remains uncured. Furthermore, the current therapy is often associated with adverse side effects and leads to a high economic burden for society. At Saverna Therapeutics, in collaboration with our partners, we initiated a lead discovery program that aims to modulate the biogenesis of miR-155. This non-coding RNA is upregulated in SLE patients and SLE mouse models. We used our drug discovery platform based on iterative fragment-based screening by nuclear magnetic resonance (NMR) and machine learning to identify ligands of pre-miR-155. After several iterations and chemical modifications, we have identified compounds that show structure-activity relationships in cellular assays. These inhibitors reduced the level of miR-155 as well as its associated inflammatory protein TNF ? whereas the cells remained viable during exposure of the compounds.

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Published

2020-10-28

How to Cite

[1]
K. Azzaoui, M. Blommers, M. Götte, K. Zimmermann, H. Liu, H. Fretz, Chimia 2020, 74, 798, DOI: 10.2533/chimia.2020.798.