PDZ proteins are a new class of drug target, operating inside the cells, which are amenable to regulation using drugs. PDZ proteins are important in numerous human diseases and are beginning to be recognized as ideal human drug targets. Many proteins in cells are tagged at their tail end, or C-terminus, with a code that instructs the cell to distribute the protein to its proper location. This code, called the PDZ ligand (PL) is read and decoded by PDZ proteins that direct the distribution of the tagged protein. Arbor Vita has identified nearly all of the PDZ domains in the human proteome and has decoded most of them. The Company has applied this knowledge to its discovery and development of novel diagnostics and therapeutics.

Importance to human biology

PDZ proteins are subunits (90-100 amino acids) of larger proteins which form defined and highly specific binding pockets. Through interactions with other proteins, PDZ proteins enable a host of critical intracellular activities including the mediation of specific protein-protein interactions that underlie the assembly of large protein complexes involved in signaling or subcellular transport. Named for the first letter of the initial three proteins in the family to be discovered (PSD-95, DLG, and ZO-1), PDZ proteins play key roles in organizing signal transduction complexes, clustering membrane receptors, and maintaining cell polarities.

Role in cell signaling

Many disease processes are associated with pathways that rely on one or more of the 300 PDZ proteins encoded by the human genome. Specifically, numerous pathogens cause disease by binding to a PDZ protein, hence disrupting normal cell signaling. The ability to regulate PDZ/PL interactions represents a novel opportunity to control multiple signaling cascades in complex diseases.