BioCentury
ARTICLE | Distillery Therapeutics

Autoimmune disease; musculoskeletal; neurology; renal

November 27, 2017 7:03 PM UTC

In vitro and cell culture studies identified a UBE2M-derived peptide inhibitor of the DCUND1-UBE2M interaction that could help treat NFE2L2-deficient diseases such MS, tissue damage, Friedreich’s ataxia and Alport syndrome. Structure-based design, chemical synthesis, in vitro testing and cell-based binding assays of analogs of a UBE2M-derived peptide yielded a compound that bound DCUND1 with a Ki of 12 nM and decreased the DCUND1-UBE2M interaction compared with an inactive control. In six human epithelial cell lines, the compound decreased levels of an E3 ubiquitin ligase complex activated by the DCUND1-UBE2M interaction and increased levels of NFE2L2, a target down-regulated by the complex. Next steps include testing the compound in models of MS, connective tissue disease associated with pulmonary arterial hypertension (PAH), Friedreich's ataxia and Alport syndrome.

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