ArticleProceedings of the National Academy of Sciences of the United States of America2022
Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed, 11 citations in OpenAlex.
- Harnessing ER-associated degradation to target transmembrane proteins.Nature reviews. Molecular cell biology · 2026Article
- Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies.International journal of molecular sciences · 2024Review
- Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing.International journal of molecular sciences · 2023Review
- Detection speed optimization of the OI-RD microscope for ultra-high throughput screening.Biomedical optics express · 2023Article
- A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development.International journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Identifying inhibitors of pathogenic proteins is the major strategy of targeted drug discoveries. This strategy meets challenges in targeting neurodegenerative disorders such as Huntington’s disease (HD), which is mainly caused by the mutant huntingtin protein (mHTT), an “undruggable” pathogenic protein with unknown functions. We hypothesized that some of the chemical binders of mHTT may change its conformation and/or stability to suppress its downstream toxicity, functioning similarly to an “inhibitor” under a broader definition. We identified 21 potential mHTT selective binders through a small-molecule microarray–based screening. We further tested these compounds using secondary phenotypic screens for their effects on mHTT-induced toxicity and revealed four potential mHTT-binding compounds that may rescue HD-relevant phenotypes. Among them, a Food and Drug Administration–approved drug, desonide, was capable of suppressing mHTT toxicity in HD cellular and animal models by destabilizing mHTT through enhancing its polyubiquitination at the K6 site. Our study reveals the therapeutic potential of desonide for HD treatment and provides the proof of principle for a drug discovery pipeline: target-binder screens followed by phenotypic validation and mechanistic studies.
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Registered trials
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