Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide.
Proc Natl Acad Sci U S A
; 119(10): e2114303119, 2022 03 08.
Article
em En
| MEDLINE
| ID: mdl-35238684
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 microarraybased 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 Administrationapproved 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desonida
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Doença de Huntington
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Proteína Huntingtina
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Mutação
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article