Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols.

Visible Light-Induced Specific Protein Reaction Delineates Early Stages of Cell Adhesion.

Light is well-established for control of bond breakage but not for control of specific bond formation in complex environments. We previously engineered the diffusion-limited reactivity of the SpyTag003 peptide with its protein partner SpyCatcher003 through spontaneous isopeptide bond formation. This system enables precise and irreversible assembly of biological building blocks with applications from biomaterials to vaccines.

Development of a light-activated STING agonist.

The STING pathway is critical to innate immunity and is being investigated as a potential therapeutic target. Existing agents targeting STING suffer from several undesirable effects, particularly the possibility of systematic activation, which increases the risk of autoimmune disorders. In this proof-of-concept study, we report the development of a light-activated STING agonist, based on the potent compound SR-717.

Isoform-specific optical activation of kinase function reveals p38-ERK signaling crosstalk.

Evolution has diversified the mammalian proteome by the generation of protein isoforms that originate from identical genes, , through alternative gene splicing or post-translational modifications, or very similar genes found in gene families. Protein isoforms can have either overlapping or unique functions and traditional chemical, biochemical, and genetic techniques are often limited in their ability to differentiate between isoforms due to their high similarity. This is particularly true in the context of highly dynamic cell signaling cascades, which often require acute spatiotemporal perturbation to assess mechanistic details.

Genetic Encoding of Arylazopyrazole Phenylalanine for Optical Control of Translation.

An arylazopyrazole was explored for its use as an enhanced photoswitchable amino acid in genetic code expansion. This new unnatural amino acid was successfully incorporated into proteins in both bacterial and mammalian cells. While photocontrol of translation required pulsed irradiations, complete selectivity for the -configuration by the pyrrolysyl tRNA synthetase was observed, demonstrating expression of a gene of interest selectively controlled via light exposure.

Visible light-induced specific protein reaction delineates early stages of cell adhesion.

Light is well established for control of bond breakage, but not for control of specific bond formation in complex environments. We previously engineered diffusion-limited reactivity of SpyTag003 peptide with its protein partner SpyCatcher003 through spontaneous transamidation. This system enables precise and irreversible assembly of biological building blocks, with applications from biomaterials to vaccines.

Peroxide-Mediated Release of Organophosphates from Boron-Containing Phosphotriesters: A New Class of Organophosphate Prodrugs.

Phosphate mono- and diesters can be liberated efficiently from boryl allyloxy (BAO) and related phosphotriesters by HO. This protocol was applied to the release of a phosphorylated serine derivative and the nucleotide analogue AZT monophosphate. Nucleotide release in the presence of ATP and a kinase provides a diphosphate, demonstrating that this method can be applied to biological processes.

Engineering SHP2 Phosphatase for Optical Control.

Signal transduction pathways are responsible for maintaining cellular functions, including proliferation, differentiation, apoptosis, and cell cycle progression. These pathways are maintained through the propagation of phosphorylation signals by protein kinases, as well as the removal of phosphorylation signals by protein phosphatases. Depending on the context, post-translational modification could have either a positive or negative effect on a signaling pathway.