Open AccessDiscovery of Small Molecule Drugs Targeting the Biogenesis of microRNA-155 for the Treatment of Systemic Lupus Erythematosus
Author(s) -
K. Azzaoui,
Marcel J. J. Blommers,
Marjo Götte,
Kaspar Zimmermann,
He Li,
Heinz Fretz
Publication year - 2020
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2020.798
Subject(s) - drug discovery , biogenesis , medicine , systemic lupus erythematosus , disease , drug , microrna , adverse effect , small molecule , autoimmune disease , computational biology , bioinformatics , immunology , cancer research , pharmacology , chemistry , biology , biochemistry , gene
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.