Cell penetrating peptides (CPP) facilitate cellular uptake of various molecular cargo emerging as attractive drug delivery tools such as the TAT peptide from Human Immunodeficiency Virus-1. The availability of a fluorescently labeled TAT penetrating peptide could benefit in the understanding of how a CPP enters a cell, and would allow us to monitor its location inside the cell through fluorescence microscopy. Here we present the photochemical synthesis of a fluorescent TAT peptide by a �one-pot-two-reactions� procedure under mild conditions. Amino acid and peptide esters with acid and base labile protecting groups have been synthesized in good yields. A TAT peptide with a photoactive C-terminal N-acyl-bromonitroindoline moiety is first irradiated with UV light in the presence of HOBt in an inert solvent producing an activated ester in situ. Then a boron-dipyrromethene (BODIPY) alcohol is introduced and acylated in the dark giving a fluorescent peptide ester. In order to allow for an on-bead installation of the fluorescent moiety, the TAT peptide was anchored to the solid support through the side chain of a C-terminal glutamic acid. Since our photochemical esterification occurs under neutral conditions, very low epimerization levels are observed. Through an epimerization study, it was observed that the esterification of dipeptides with alanine and glutamic acid at the C-terminal produced less than 1% of epimerized product.

Synthesis of a fluorescently labeled TAT peptide with reduced epimerization through a novel photochemical method

246th National Meeting (2013)

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