Phosphate Isosteres in Medicinal Chemistry

The phosphate group is at the heart of an enormous number of biological processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biological activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognise the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chemistry research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognising domains such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilisation of the phosphate moiety as part of an inhibitor is severely limited by the enzymatic lability and poor cell