Multi phosphorylated peptides: Importance, Synthetic Strategies, and applications for studying biological mechanisms

Unraveling the role of post translational modifications (PTM) patterns is one of the most urgent and unresolved issues facing the chemical biology community. Attempts to crack the phosphorylation bio-barcode has been leading to significant findings. These studies suggest that many proteins cannot be regarded as a single entity but exist as several forms which differs in their phosphorylation pattern and their function. While protein regions which does not contain PTMs can be rather simply mimicked using peptide libraries, heavily phosphorylated regions are much harder to study using the same tools. The differences between the syntheses of simple phosphopeptides to the synthesis of multiphosphopeptides are dramatic. The synthesis of multiphosphopeptides is a major synthetic challenge and many strategies have been developed to provide a route to enable their preparation. In this review, we specifically emphasize the challenges and importance of synthesizing multiphosphopeptides and their libraries. Historical perspective and the state of the art strategies are described. The advantages and disadvantages of each strategy are discussed in order to provide a roadmap for the synthesis of such libraries. An overview of the existing strategies is provided as well as some comments regarding future directions Applications of multiphosphopeptides libraries as tools to study the effect of phosphorylation patterns on biological function of proteins are also described.