Search

In this issue of Chemistry & Biology, Arrendale and coworkers demonstrate a new prodrug strategy for intracellular delivery of an α, α-(difluoromethylene)phosphonate phosphoserine mimic. The deprotected pseudo-phosphopeptide releases the pro-apoptotic FOXO3a-transcription factor from its 14-3-3-adaptor protein complex, resulting in leukemic cell death., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This overview focuses on the (alpha,alpha-difluoromethylene)phosphonate mimic of phosphoserine (pCF(2)Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF(2)-C bond formation. The pCF(2)-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chemical biological approach include the regulation of p53 tumor suppressor protein activity and of melatonin production. Given these successes, the future is bright for the use of such "teflon phospho-amino acid mimics" to map kinase-based signaling pathways.