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Approach
PDZ protein interactions are ideal drug targets
in that each PDZ protein binds to its respective PDZ ligand (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 discovered
to target kinases (viruses) 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. Arbor Vita is developing
a PDZ-based treatment for stroke 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, Arbor Vita can optimize candidate drugs by pre-screening
compounds for those that selectively inhibit only the targeted
interaction, virtually eliminating 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. Arbor Vita has two diagnostic products in
pre-clinical development: AVC Dx-1
for diagnosis of cervical cancer and AVC
Dx-2 for rapid, point-of-care testing for avian influenza
in humans.
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