Open AccessSuppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide
Author(s) -
Haikun Song,
Cen Wang,
Chenggang Zhu,
Ziying Wang,
Huiya Yang,
Peng Wu,
Xiaotian Cui,
Juan Botas,
Yongjun Dang,
Yu Ding,
Yiyan Fei,
Boxun Lu
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2114303119
Subject(s) - huntingtin , drug discovery , biology , huntingtin protein , mutant , toxicity , phenotype , computational biology , phenotypic screening , small molecule , drug development , drug , chemistry , genetics , pharmacology , biochemistry , gene , organic chemistry
Significance Classical drug discovery identifies inhibitors that block the activities of pathogenic proteins. This typically relies on a measurable biochemical readout and accessible binding sites whose occupancy influences the activity of the target protein. These requirements make many pathogenic proteins “undruggable.” Here, we report a strategy to target these undruggable proteins: screening for compounds that directly bind to the undruggable target and rescue disease-relevant phenotypes. These compounds may suppress the target’s pathogenic functions via direct binding to it. We applied this strategy to the mutant HTT protein, which is an undruggable protein that causes Huntington’s disease (HD). We revealed desonide, an FDAapproved drug, as a possible lead compound for HD drug discovery.