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High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
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High-Throughput Screening for Epigenetic Compounds That Induce Human β-Defensin 1 Synthesis
Wentao Lyu1,2, Zhuo Deng2,3, Guolong Zhang2
1State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Agro-Product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China.
Antibiotics (Basel, Switzerland)
|February 25, 2023
Summary
Researchers identified small molecules that boost antimicrobial host defense peptides (HDPs), like human beta-defensin 1 (DEFB1). Benzamide-based histone deacetylase inhibitors (HDACi) show promise for developing new antimicrobial therapies.
Area of Science:
- Innate immunity and host defense mechanisms.
- Drug discovery and development.
- Molecular biology and gene regulation.
Background:
- Antimicrobial host defense peptides (HDPs) are crucial for innate immunity.
- Small molecules that induce HDP synthesis are potential antimicrobial therapies.
- Targeting human beta-defensin 1 (DEFB1) gene transcription is a key strategy.
Purpose of the Study:
- To discover small molecules that specifically activate human beta-defensin 1 (DEFB1) gene transcription.
- To establish a high-throughput screening assay for identifying DEFB1 inducers.
- To explore the potential of epigenetic compounds in antimicrobial therapy.
Main Methods:
- Development of a stable HT-29/DEFB1-luc reporter cell line.
- High-throughput screening of 148 small-molecule epigenetic compounds.
- Confirmation of DEFB1 mRNA induction in HT-29 cells and analysis of CAMP gene expression.
Main Results:
- Identified 28 hit compounds, with 14 confirmed to induce DEFB1 mRNA expression.
- Observed co-induction of the human cathelicidin antimicrobial peptide (CAMP) gene.
- Benzamide-containing histone deacetylase inhibitors (HDACi) emerged as potent HDP inducers.
- Differential regulation of intestinal barrier genes (claudins, TJP1, MUC2) by HDP inducers.
Conclusions:
- Benzamide-based HDAC inhibitors are effective inducers of HDP synthesis.
- These compounds show potential as host-directed antimicrobials for infectious disease control.
- Epigenetic modulation offers a promising avenue for developing novel antimicrobial strategies.
