药物再利用筛选发现多巴胺信号传导是治疗罕见病 DPAGT1-CDG 的潜在疗法的关键途径。

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI:10.1371/journal.pgen.1011458
Hans M Dalton, Naomi J Young, Alexys R Berman, Heather D Evans, Sydney J Peterson, Kaylee A Patterson, Clement Y Chow
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引用次数: 0

摘要

DPAGT1-CDG 是一种缺乏有效疗法的先天性糖基化紊乱(CDG)。它是由编码 N-连接糖基化第一酶的 DPAGT1 基因突变引起的。我们使用了一种果蝇粗眼模型,该模型中的DPAGT1-CDG具有发育不全的小眼睛表型。我们对该模型进行了药物再利用筛选,使用了 1,520 种 98% 已获 FDA/EMA 批准的小分子药物,以寻找能改善其眼睛的药物。我们发现了 42 种可改善 DPAGT1-CDG 模型的候选药物。值得注意的是,在这次筛选中,我们发现多巴胺 D2 受体的药理和基因抑制可部分挽救 DPAGT1-CDG 模型。多巴胺合成和再循环的缺失也部分挽救了该模型,这表明在 DPAGT1 缺乏的情况下,多巴胺能通量以及随后与 D2 受体的结合是有害的。这将多巴胺信号转导与 N-糖基化联系起来,成为治疗 DPAGT1-CDG 的一个新的潜在治疗靶点。我们还从基因上验证了其他顶级药物类别,包括乙酰胆碱相关药物、COX 抑制剂和 NKCC1 抑制剂。这些药物和后续分析揭示了 DPAGT1 机制中的新生物学特性,它们可能是 DPAGT1-CDG 的新治疗方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A drug repurposing screen reveals dopamine signaling as a critical pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.

DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies. It is caused by mutations in the gene DPAGT1 which encodes the first enzyme in N-linked glycosylation. We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype. We performed a drug repurposing screen on this model using 1,520 small molecules that are 98% FDA/EMA-approved to find drugs that improved its eye. We identified 42 candidate drugs that improved the DPAGT1-CDG model. Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model. Loss of both dopamine synthesis and recycling partially rescued the model, suggesting that dopaminergic flux and subsequent binding to D2 receptors is detrimental under DPAGT1 deficiency. This links dopamine signaling to N-glycosylation and represents a new potential therapeutic target for treating DPAGT1-CDG. We also genetically validate other top drug categories including acetylcholine-related drugs, COX inhibitors, and an inhibitor of NKCC1. These drugs and subsequent analyses reveal novel biology in DPAGT1 mechanisms, and they may represent new therapeutic options for DPAGT1-CDG.

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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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