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

• Main Authors: Wentao Lyu (Author), Zhuo Deng (Author), Guolong Zhang (Author)
• Format: Book
• Published: MDPI AG, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 β-defensin 1 (<i>DEFB1</i>) gene transcription, we established a cell-based high-throughput screening assay that employs HT-29/<i>DEFB1-luc</i>, a stable reporter cell line expressing the luciferase gene driven by a 3-Kb <i>DEFB1</i> 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 <i>DEFB1</i> mRNA expression in human HT-29 colonic epithelial cells. Desirably, the human cathelicidin antimicrobial peptide (<i>CAMP</i>) 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.

Item Description

10.3390/antibiotics12020186
2079-6382