Publication date: Nov 01, 2019
The team carried out a smartly designed screening featuring a small-molecule microarray and front-edge optical technologies, and managed to identify four small molecule compounds that specifically reduced the protein that causes Huntington’s disease.
“Small molecule glue” helps autophagosomes “engulf” the disease-causing protein Since the conventional approach is infeasible for mHTT, the team came up with a fundamentally new idea, which was to degrade mHTT by harnessing autophagy, an intracellular protein degradation process.
To identify compounds that only degrade mHTT but not wild-type HTT, the team envisioned a “small molecule glue” functioning as an “autophagosome tethering compound” (ATTEC), which could tether LC3 and mHTT together so that mHTT is engulfed into autophagosomes for degradation.
The team found that these four compounds significantly reduced mHTT levels in HD mouse neurons, HD patient cells, and HD drosophila models at ~10 to 100 nanomolar concentrations, with little effect on wild-type HTT levels.
Using this cutting-edge screening approach, the team found two small molecules that could bind to both LC3 and mHTT proteins, but not to wild-type HTT.
Autophagosome tethering compounds may open new windows for drug discovery The team further explored the intrinsic mechanisms by which these small molecule compounds could distinguish between mutant and wild-type HTT proteins, which were almost identical except in the glutamine repeat (polyQ) length.
Based on this, the team realized that the application of these small molecule compounds may reach far beyond the potential treatment of Huntington’s disease.
With SCA3 patient cells provided by Dr. Yimin Sun from Prof. Jian Wang’s group at Huashan Hospital affiliated to Fudan University, the team found that these compounds could effectively reduce the level of the mutant ATXN3 protein (with a polyQ length of 74) that causes the disease, without affecting the wild-type ATXN3 (with a polyQ length of 27).
The new concept of drug development using autophagosome-binding compounds (ATTEC) may also be applied to other pathogenic proteins that are undruggable, or even to pathogenic substances that are not proteins, such as organelles or lipids. “