Academic Journal
Targeting AGAT gene expression - a drug screening approach for the treatment of GAMT deficiency
| العنوان: | Targeting AGAT gene expression - a drug screening approach for the treatment of GAMT deficiency |
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| المؤلفون: | Tkachyova, Ilona, Tropak, Michael B, Lee, Alex, Datti, Alessandro, Ito, Shinya, Schulze, Andreas |
| المساهمون: | Tkachyova, Ilona, Tropak, Michael B, Lee, Alex, Datti, Alessandro, Ito, Shinya, Schulze, Andreas |
| سنة النشر: | 2024 |
| المجموعة: | IRIS Università degli Studi di Perugia |
| مصطلحات موضوعية: | AGAT gene repression, GAMT deficiency, HAP1 AGAT gene NLuc reporter fusion, HeLa AGAT promoter FLuc reporter cells, drug screening |
| الوصف: | Background: Targeting the enzyme L-Arginine:glycine amidinotransferase (AGAT) to reduce the formation of guanidinoacetate (GAA) in patients with guanidinoacetate methyltransferase (GAMT) deficiency, we attempted to identify drugs for repurposing that reduce the expression of AGAT via transcriptional inhibition. Research Design and Methods: The authors applied a HeLa cell line stably expressing AGAT promoter and firefly luciferase reporter for high-content screening and secondary screening. For further assessment, the authors integrated Nanoluc luciferase as a reporter into the endogenous AGAT gene in HAP1 cell lines and used the human immortalized cell line RH30 as model of GAMT deficiency. Results: Screening 6,000 drugs and drug-like compounds, the authors identified 43 and 34 high-score candidates as inhibitors and inducers of AGAT promoter-reporter expression, respectively. After further deselection considering dose response, drug toxicity, topical formulations, price, and accessibility, the authors assessed seven candidates and found none of them demonstrating efficacy in HAP1 and RH30 cells and warranting further assessment. Conclusion: The selection of the test models is crucial for screening of gene repressor drugs. Almost all drugs with an impact on gene expression had off-target effects. It is unlikely to find drugs that are selective inhibitors of AGAT expression, rendering pharmacological AGAT gene repression a risky approach for the treatment of GAMT deficiency. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | ELETTRONICO |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/39402976; info:eu-repo/semantics/altIdentifier/wos/WOS:001331880400001; firstpage:1; lastpage:15; numberofpages:15; journal:EXPERT OPINION ON DRUG DISCOVERY; https://hdl.handle.net/11391/1586401 |
| DOI: | 10.1080/17460441.2024.2412994 |
| الاتاحة: | https://hdl.handle.net/11391/1586401 https://doi.org/10.1080/17460441.2024.2412994 https://www.tandfonline.com/doi/full/10.1080/17460441.2024.2412994 |
| رقم الانضمام: | edsbas.E6625F75 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1080/17460441.2024.2412994 |
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