Inositol pyrophosphates (PP-IPs) act as second messengers in intracellular signaling pathways and are necessary for normal insulin sensitivity and fat storage. It was recently discovered that these reactive metabolites transduce their signal by a novel post-translational modification known as pyrophosphorylation. Because the study of pyrophosphorylation has proven intractable to existing analysis techniques, a method for the synthesis of pyrophosphorylated peptides and proteins is necessary to develop new chemical tools to elucidate the signaling pathways of PP-IPs. Earlier this year, we reported that phosphorimidazolide chemistry provides a highly selective and convenient method for the synthesis of pyrophosphorylated peptides. Strikingly, the pyrophosphorylation methodology is compatible with reactive groups on peptide substrates (alcohols, phenols, thiols, amines, carboxylic acids) and is able to operate in polar solvents, including water, under mild conditions. The utility of phosphorimidazolide reagents has been expanded through the use of photo-labile and acid-labile protecting groups that enable pyrophosphorylation of entire proteins. The unique bio-selective reactivity profile of phosphorimidazolide reagents opens the door to selective modification of phosphorylated protein and peptide substrates for a diversity of applications.

Pyrophosphorylation of peptides and proteins using phosphorimidazolides

249th National Meeting (2015)

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