Approach

PDZ protein interactions are ideal drug targets in that each PDZ protein binds to its respective PDZ ligands (PL) in a discrete, well-defined and well-characterized binding pocket. The last four amino acids at the C-terminus of the PL selectively bind in the PDZ pocket. The interaction is analogous to a "lock-and-key" enzyme pocket where small-molecule therapeutics have been designed to target kinases (cancer) and proteases (HIV/AIDS). Scientists at Arbor Vita Corporation have demonstrated that disrupting the PDZ/PL interaction can inactivate critical signaling pathways within disease pathways, establishing the basis for developing new therapeutics.

Alternative drug targets

PDZ interactions may offer an alternative route to affect many already validated targets. As an example, nearly half of all FDA-approved drugs modulate the function of a family of cell receptors called G-protein coupled receptors (GPCRs). About one third of all GPCRs are organized inside the cell by PDZs, suggesting that drugs directed against such GPCR/PDZ interactions may offer an alternative intervention treatment modality.

Favorable side-effect profile

Unfavorable side effects are the leading cause of failure of drugs in clinical trials. AVC is developing a PDZ-based treatment for neuroischemia and traumatic brain injury that, due to its unique mechanism of action, has the potential to eliminate many of the problems associated with current therapies. The company's PDZ platform may provide solutions in three major ways:

Cell surface receptors that are organized inside the cell by PDZ proteins may be targeted through the PDZ interaction inside the cell to minimize side effects.

Often expressed only in limited cell types, PDZ proteins and their respective PDZ ligands make possible the development of specific therapeutics targeting only those cells, reducing the likelihood of side effects stemming from the inadvertent disruption of unrelated interactions.

With its extensive library of PDZ protein interactions, AVC can optimize candidate drugs by pre-screening compounds for those that selectively inhibit only the targeted interaction, greatly reducing the potential side effects stemming from the unintended disruption of similar PDZ protein interactions.

Novel Diagnostics

PDZ domain pockets bind their protein ligand partners with very high affinity. In many cases, the strength of the binding affinity is equivalent to that of a monoclonal antibody. This property is the basis for the company's broad diagnostic platform for the detection of pathogens and proteins which are overexpressed or altered in certain diseases. Importantly, the strong binding affinity of PDZ proteins to their PDZ ligands presents the opportunity to develop both novel diagnostics and therapeutics. Such pairings can greatly increase the success of therapeutics during and following clinical trials by identifying patients that would most benefit.

In April 2009, AVC received 510(k) clearance from the FDA for the first rapid test for avian influenza in humans: the AVantage™ A/H5N1 Flu Test. The company also has a diagnostic product for cervical cancer in preclinical development. The AVC AVantage HPV E6 Test is intended for developing countries and has been supported through collaboration with the Program for Appropriate Technology in Health (PATH).