High-Throughput Screening for Epigenetic Compounds That Induce Human beta-Defensin 1 Synthesis

文献类型： 外文期刊

第一作者： Lyu, Wentao

作者： Lyu, Wentao;Lyu, Wentao;Deng, Zhuo;Zhang, Guolong;Deng, Zhuo

作者机构：

关键词： antimicrobial peptides; epigenetic compounds; high-throughput screening; histone deacetylase inhibitors; host defense peptides

期刊名称：ANTIBIOTICS-BASEL （ 影响因子：4.8； 五年影响因子：4.9 ）

ISSN： 2079-6382

年卷期： 2023 年 12 卷 2 期

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收录情况： SCI

摘要： Antimicrobial host defense peptides (HDPs) are critically important for innate immunity. Small-molecule compounds with the ability to induce HDP synthesis are being actively explored for antimicrobial therapy. To facilitate the discovery of the compounds that specifically activate human beta-defensin 1 (DEFB1) gene transcription, we established a cell-based high-throughput screening assay that employs HT-29/DEFB1-luc, a stable reporter cell line expressing the luciferase gene driven by a 3-Kb DEFB1 gene promoter. A screening of a library of 148 small-molecule epigenetic compounds led to the identification of 28 hits, with a minimum strictly standardized mean difference of 3.0. Fourteen compounds were further selected and confirmed to be capable of inducing DEFB1 mRNA expression in human HT-29 colonic epithelial cells. Desirably, the human cathelicidin antimicrobial peptide (CAMP) gene was also induced by these epigenetic compounds. Benzamide-containing histone deacetylase inhibitors (HDACi) were among the most potent HDP inducers identified in this study. Additionally, several major genes involved in intestinal barrier function, such as claudin-1, claudin-2, tight junction protein 1, and mucin 2, were differentially regulated by HDP inducers. These findings suggest the potential for the development of benzamide-based HDACi as host-directed antimicrobials for infectious disease control and prevention.

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