Development of sulfonium tethered peptides conjugated with HDAC inhibitor to improve selective toxicity for cancer cells. (1st April 2023)

• Record Type: Journal Article
• Authors: Du, Li; Song, Chunli; Du, Jingjing; Zeng, Fang; Zhang, Yu; Yin, Feng; Li, Zigang; Wang, Dongyuan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 83(2023)
• Publication Date: 2023-04-01
• Subjects: Stabilized peptide -- Sulfonium -- HDAC inhibitor -- Cancer selectivity -- Lytic peptide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117213
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: A sulfonium tethered multifunctional peptide drug conjugates (PDCs) was developed, which showed selectivity to cancer cells through chemical modification of lytic peptide and conjugation with HDAC inhibitor. Abstract: The anti-cancer peptides emerged as new weapons for cancer therapy due to their potent toxicity toward various cancer cells. However, their therapeutic promise is often limited by non-specific toxicity to normal cells. How to improve peptides' selectivity to cancer cells is always a matter to solve. In this manuscript, we designed a sulfonium tethered lytic peptide conjugated with a HDAC inhibitor to improve the selectivity of cancer cells. The sulfonium tethered lytic peptide with improved hydrophilicity and positive charge showed reduced toxicity to both cancer cells and normal cells. When conjugated with the HDAC inhibitor, this peptide showed increased toxicity to cancer cells. Besides, the stabilized peptide HDAC conjugate showed better serum stability than the linear peptide conjugate. For cellular function, the stabilized peptide conjugate could induce cancer cell apoptosis, cell cycle arrest, and influence multiple signal pathways through transcriptome analysis. This design may provide an alternative approach for the development of safe and effective anti-cancer drugs.