Peptide-inspired inhibitors of C-mannosyltransferases

Goddard-Borger ED1,2

  1. The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.

Tryptophan mannosylation is an unusual co-translational modification that promotes protein folding and enhances the stability of some type-I cytokine receptors. This protein modification is installed by two integral membrane enzymes that are localised to the ER and encoded by dpy19l1 and dpy19l3. Perturbing tryptophan mannosylation dramatically reduces the cell surface expression of TPOR and IL7R: cytokine receptors whose constitutive expression drives the proliferation of some blood cancers (e.g. MPNs and T-ALL). We have developed small molecule inhibitors of C-mannosyltransferases to determine if pharmacological inhibition of tryptophan mannosylation might be useful for treating some blood cancers. To accomplish this, we established in vitro C-mannosyltransferase activity assays and probed the enzyme’s peptide substrate preferences in detail. SAR studies then guided us in the conversion of a tetrapeptide substrate of the enzyme into a non-peptide inhibitor of tryptophan mannosylation with low micromolar activity in cells.