NAAG peptidase inhibitors and their potential for diagnosis and therapy

  title={NAAG peptidase inhibitors and their potential for diagnosis and therapy},
  author={Jia Zhou and Joseph H Neale and Martin G. Pomper and Alan P. Kozikowski},
  journal={Nature Reviews Drug Discovery},
Modulation of N-acetyl-L-aspartyl-L-glutamate peptidase activity with small-molecule inhibitors holds promise for a wide variety of diseases that involve glutamatergic transmission, and has implications for the diagnosis and therapy of cancer. This new class of compounds, of which at least one has entered clinical trials and proven to be well tolerated, has demonstrated efficacy in experimental models of pain, schizophrenia, amyotrophic lateral sclerosis, traumatic brain injury and, when… 

Therapeutic Indications of NAAG Peptidase Inhibitors for Parkinson’s Disease

  • Lin Zhang
  • Biology
    Archives in Neurology & Neuroscience
  • 2021
Results reveal that NAAG Peptidase Inhibitors could assist clinicians in understanding the pathophysiology of PD leading to a more effective treatment of patients’ symptoms and could potentially accelerate early stages of PD interventions.

Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders

This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.

Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies

Monitoring GCP activity in human skin after administration of G CP inhibitors could be readily used as PD marker in the clinical development of GCP inhibitors.

Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer.

This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies, and outlines the development of G CPII-specific small-molecule compounds and their use in preclinical and clinical settings.

N-Acetylaspartate and N-acetylaspartylglutamate

In conclusion, elucidation of the neurobiology of NAA and NAAG provides insight into the role of these molecules in the pathophysiology of several neurologic disorders and their potential as a therapeutic target for these conditions.

Design, synthesis and pharmacological activity of novel enantiomerically pure phosphonic acid-based NAALADase inhibitors.

A series of novel enantiomerically pure 2-(phosphonomethyl)pentanedioic acid (2- PMPA) based NAALADase inhibitors were synthesized and showed activity similar to the known potent inhibitor (S)-2-PMPA.

Antipsychotic drugs increase N‐acetylaspartate and N‐acetylaspartylglutamate in SH‐SY5Y human neuroblastoma cells

High performance liquid chromatography is used to determine the effects of the antipsychotic drugs haloperidol and clozapine on NAA and NAAG levels in SH‐SY5Y human neuroblastoma cells, a model system used to test the responses of dopaminergic neurons in vitro.

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer




Synthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents.

A series of potent, urea-based GCPII inhibitors from the lead compound 3 are synthesised and data revealing the ability of one of these compounds, namely, 8d, to reduce the perception of inflammatory pain is provided.

Design and pharmacological activity of phosphinic acid based NAALADase inhibitors.

The data suggest that NAALADase inhibition may provide a new approach for the treatment of both neurodegenerative disorders and peripheral neuropathies.

Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated alpha-linked acidic dipeptidase.

Inhibition of NAALADase may show utility as a therapeutic intervention in diseases in which altered levels of glutamate are thought to be involved, and is suggested to act as a storage form of synaptic glutamate.


It is speculated that one role for NAAG following synaptic release is the activation of metabotropic autoreceptors that inhibit subsequent transmitter release, and a second role is the production of extracellular glutamate following N AAG hydrolysis.

Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase

The 3.5-Å crystal structure of the PSMA ectodomain is presented, which reveals a homodimer with structural similarity to transferrin receptor, a receptor for iron-loaded transferrin that lacks protease activity.

Molecular modeling of the interactions of glutamate carboxypeptidase II with its potent NAAG-based inhibitors.

The structure-based design of GCPII in complex with its potent inhibitors 2-(phosphonomethyl)pentanedioic acid (PMPA) and 4,4'-phosphinicobis(butane-1,3-dicarboxylic acid) (PBDA) were built by a computational docking method and the predicted binding mode is consistent with the experimental data obtained from site-directed mutagenesis.

Synthesis and biological evaluation of thiol-based inhibitors of glutamate carboxypeptidase II: discovery of an orally active GCP II inhibitor.

The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury

It is demonstrated that the newly described 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion, indicating that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.