The Amiloride Derivatives Regulate the Alternative Splicing of Apoptotic Gene Transcripts

Abstract

Alternative splicing of precursor mRNA is an important mechanism for increasing the complexity of gene expression, and it plays a key role in cell differentiation and organism development. Accurate alternative splicing profiles and regulation will affect the cellular functions and destiny. Our previous studies showed that amiloride have a potential effect on alternative splicing, but the high effective concentration of amiloride limits its clinical application. In this study, the molecular docking calculation was performed to estimate the binding affinity between a series synthesized amiloride derivatives and SRPK1 protein in silico and then detect its activity in alternative splicing in vitro. The results showed that amiloride derivatives DS010, DS150, and ES013 have better binding affinity and could regulate the alternative splicing of BCL-X transcripts to increase the proportion of BCL-XL in Huh-7 cells. In addition, the effective concentration of DS010 and ES013 are lower than others. These findings suggested that the amiloride derivative DS010 and ES013 may provide therapeutic potential for future cancer treatment.