Screening of ~2500 small molecules identified several compounds, including palmitoylethanolamide and GW0742, that prevent protease-induced degradation of wildtype and variant desmoplakin in vitro.
Identification of small molecules that physically block calpain accessibility to desmoplakin lays the groundwork for pharmacological treatment of hypersensitive DSP variants.
variants, disease is linked to calpain hypersensitivity. Previous studies show that calpain hypersensitivity can be corrected in vitro through the addition of a bulky residue neighboring the cleavage site, suggesting that physically blocking calpain accessibility is a viable strategy to restore DSP levels. Here, we aim to find drug-like molecules that also block calpain-dependent degradation of DSP. To do this, we screened ~2500 small molecules to identify compounds that specifically rescue DSP protein levels in the presence of proteases. We find that several molecules, including sodium dodecyl sulfate, palmitoylethanolamide, GW0742, salirasib, eprosarten mesylate, and GSK1838705A prevent wildtype and disease-variant-carrying DSP protein degradation in the presence of both trypsin and calpain without altering protease function. Computational screenings did not predict which molecules would protect DSP, likely due to a lack of specific DSP-drug interactions. Molecular dynamic simulations of DSP-drug complexes suggest that some long hydrophobic molecules can bind in a shallow hydrophobic groove that runs alongside the protease cleavage site. Identification of these compounds lays the groundwork for pharmacological treatment for individuals harboring these hypersensitive DSP variants.
Romov et al. (Wed,) conducted a other in Desmoplakin (DSP) variants linked to calpain hypersensitivity. Small molecules (e.g., palmitoylethanolamide, GW0742, salirasib) was evaluated on Rescue of DSP protein levels in the presence of proteases. Screening of ~2500 small molecules identified several compounds, including palmitoylethanolamide and GW0742, that prevent protease-induced degradation of wildtype and variant desmoplakin in vitro.