A novel mRNA decay inhibitor abolishes pathophysiological cellular transition

Abstract

In cells, mRNA synthesis and decay are influenced by each other, and their balance is altered by either external or internal cues, resulting in changes in cell dynamics. We previously reported that it is important that an array of mRNAs that shape a phenotype are degraded before cellular transitions, such as cellular reprogramming and differentiation. In adipogenesis, the interaction between DDX6 and 4E-T had a definitive impact on the pathway in the processing body (PB). We screened a library of α-helix analogs with an alkaloid-like backbone to identify compounds that inhibit the binding between DDX6 and 4E-T proteins, which occurs between the α-helix of structured and internally disordered proteins. IAMC-00192 was identified as a lead compound. This compound directly inhibited the interaction between DDX6 and 4E-T. IAMC-00192 inhibited the temporal increase in PB formation that occurs during adipogenesis and epithelial-mesenchymal transition (EMT) and significantly suppressed these cellular transitions. In the EMT model, the half-life of preexisting mRNAs in PBs was extended twofold by the compound. The novel inhibitor of RNA decay not only represents a potentially useful tool to analyze in detail the pathological conditions affected by RNA decay and how it regulates the pathological state. The identification of this inhibitor may lead to the discovery of a first-in-class RNA decay inhibitor drug.

Peptide-encoding gene transfer to modulate intracellular protein-protein interactions

“…We previously found an association between DDX6 and 4ET, which plays a central role in RNA decay in RNA metabolism. 10 Subsequently, we found that RNA decay regulates adipogenic differentiation by inhibiting the intracellular PPI of DDX6 and 4ET using peptidomimetics with a novel cage-like chemical skeleton. 10 Peptides and peptidomimetics, including ours, can elicit useful effects against intracellular PPIs if they can be stably introduced into cells, but cell membrane permeation is a major barrier that limits peptide drugs from reaching the clinic.…”

“… 10 Subsequently, we found that RNA decay regulates adipogenic differentiation by inhibiting the intracellular PPI of DDX6 and 4ET using peptidomimetics with a novel cage-like chemical skeleton. 10 Peptides and peptidomimetics, including ours, can elicit useful effects against intracellular PPIs if they can be stably introduced into cells, but cell membrane permeation is a major barrier that limits peptide drugs from reaching the clinic. One example is ALRN-6924, which was developed to inhibit the association of the tumor suppressor p53 with its inhibitory proteins, MDM2 and MDMX.…”

“… 8 Thus far, modifications have been developed based on sequence to improve stability, cell membrane permeability, and binding ability, 9 as have mimetics in which the backbone is replaced with artificial materials. 10 In addition, cyclic peptides, which are more cell permeable than linear peptides, show great potential. 11 Nevertheless, the cell membrane is still an extremely large barrier to modification of intracellular PPIs, and the cyclic form and modification of peptides pose problems specific to each peptide.…”

Exploring the role of transcriptional and post‐transcriptional processes in mRNA co‐expression

“…Experimentally this would be possible by perturbing specific kinetic steps of gene expression followed by single-cell transcriptomic and proteomic studies, that could provide interesting insights. [81][82][83][84] While small molecules with mRNA degradation inhibition functions are only just starting to be characterized, [85] transcript(s) specific perturbations (e.g., through the use of miRNA sponges [86] ) or inhibitors of nonsense-mediated mRNA decay [87,88] are already available. The implication of blocking transcript-shared mechanisms is perhaps a little less clear.…”