Biomedical Engineering Reference
In-Depth Information
3.7.1.2 NAAG Analogs
Although glutamate-based inhibitors have shown their utility in several
experimental setups, probing both specificity pockets (S1 and S1
0
) simulta-
neously offers more space for diversification and fine tuning of inhibitor
properties as well as the attachment of functional groups required for specific
applications (e.g. NIR-imaging, SPECT, antibody recruitment). Consequently,
inhibitors based on the NAAG scaffold are gaining prominence in the field.
This class of inhibitors features non-hydrolyzable peptide bond surrogates,
i.e. zinc-binding functionalities replacing the peptide bond of NAAG that can
mimic either the planar peptide bond (ureas) or tetrahedral transition state
intermediate (phosphorus-containing groups). The use of phosphonate and
phosphinate analogs was pioneered by Jackson and later by the Slusher
group.
11,13,89,92,93
Extensive SAR studies led to the identification of several
drug candidates, such as GPI5232,
94,95
used as a scaffold for the synthesis of
NIR imaging probes (such as GPI-78).
96
Phosphorus chemistry (phosphona-
midates in this case) was also used by the Berkman group for the preparation of
compounds used for photodynamic therapy.
97
Urea-based GCPII inhibitors
were first reported by the Kozikowski group.
98
Urea chemistry was used for
inhibitors in several diverse applications—the experimental treatment of neu-
rodegenerative conditions (ZJ series);
99-101
PET/SPECT imaging of prostate
cancer in preclinical (and clinical) studies (Pomper group);
102-107
and the
recruitment of autologous antibodies to prostate cancer cells expressing GCPII
(ARMs, Spiegel group).
84,108
3.7.1.2.1 Prototypical NAAG-Based Inhibitor. The common denominator
of the majority of NAAG-based inhibitors, irrespective of the surrogate
chemistry, is the presence of glutamate in the P1
0
position, although several
other residues have been tested with variable results. The P1
0
glutamate
ensures inhibitor specificity and productive positioning within the substrate
binding pocket and contributes markedly to the overall anity. The peptide
bond (or transition state) surrogates that connect the P1
0
and P1 parts inter-
act with the active-zinc ions and with Glu424.
Note: for the purpose of this review, the D-part (or D-moiety) will be broadly
defined as the part of an NAAG-based inhibitor that is connected to the P1
0
glutamate via the peptide bond (or transition state) surrogate. The D-part typi-
cally includes a linker together with a distal functional group or, alternatively,
moieties that would be equivalent to the P1, P2 ...Pn residues of a hypothetical
peptidic substrate.
The major variability among the NAAG-based inhibitors is observed in their
distal parts (D-parts), with a single exception: the majority of inhibitors feature
a proximal P1 carboxylate group that intimately interacts with the arginine
patch and contributes to inhibitor anity for the enzyme by mimicking P1
carboxylates of GCPII substrates. Additional fine-tuning of the inhibitor
potency for GCPII is influenced by a 'productive' combination of linker length
and the physicochemical properties of
the distal
functional group. The
