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NAAG peptidase inhibitors and their potential for diagnosis and therapy

Key Points

  • Glutamate (Glu) is the most abundant excitatory transmitter in the central nervous system. However, excessive glutamatergic transmission can damage or kill neurons, and has therefore been implicated in a variety of neurological disorders.

  • N-Acetyl-L-aspartyl-L-glutamate (NAAG), one of the three most prevalent neurotransmitters, acts as an agonist at group II metabotropic glutamate receptors with preference for metabotropic glutamate (mGlu3) receptors on neurons and glia. Two extracellular enzymes, glutamate carboxypeptidase II and III (GCPII and III), hydrolyse NAAG to N-acetylaspartate (NAA) and glutamate following its release into the synaptic cleft.

  • Inhibition of these NAAG peptidases (NPs) is thought to provide neuroprotection by increasing the intrasynaptic concentration of NAAG. NAAG decreases the release of glutamate by activation of presynaptic group II mGlu receptors and stimulates release of trophic factors from glia. Those actions of NAAG may provide neuroprotection in clinical conditions in which glutamate mediates and mGlu3 receptor activation reduces pathology.

  • Importantly, NP inhibitors do not seem to affect normal glutamate function. NP inhibition enhances a natural ongoing regulatory process rather than chronically activating or inhibiting receptors in a manner that is unrelated to ongoing chemical neurotransmission. NP represents an intriguing target for drug discovery aimed at unmet medical needs.

  • Additionally, human GCPII has also been identified as prostate-specific membrane antigen (PSMA), a cell surface protein expressed in elevated levels by prostate cancer. Its X-ray crystal structure was recently reported.

  • Studies using small-molecule-based NP inhibitors have confirmed their beneficial effects in animal models relevant to neurodegenerative diseases as well as cancer.

  • NP inhibitors therefore have significant potential for use as both diagnostic and therapeutic agents. Specific applications include neuropathic and inflammatory pain, traumatic brain injury, ischemic stroke, schizophrenia, diabetic neuropathy, amyotrophic lateral sclerosis, drug addiction, as well as prostate cancer.

Abstract

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 appropriately functionalized, can image prostate cancer. Further investigation of these promising drug candidates will be needed to bring them to the marketplace. The recent publication of the X-ray crystal structure for the enzymatic target of these compounds should facilitate the development of other new agents with enhanced activity that could improve both the diagnosis and treatment of neurological disorders.

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Figure 1: Metabotropic glutamate (mGlu) receptor subtypes.
Figure 2: Mechanism of NAAG action on presynaptic endings.
Figure 3: Structure model of the GCPII extracellular domain.
Figure 4: Crystal structural of prostate-specific mebrane antigen: ribbon diagrams of side and top view.
Figure 5: Selected small-molecule-based NAAG peptidase inhibitors.
Figure 6: Complex model between GCPII and PBDA.
Figure 7: Chemical structures of two radiolabelled urea-based potent NAAG peptidase inhibitors.
Figure 8: Small animal imaging of [11C]DCMC and [125I]DCIT in experimental prostate cancer.

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Acknowledgements

The authors thank W. Tueckmantel of Acenta Discovery, Inc. for helpful discussions. This work was supported by the National Institutes of Health (NIH), including a National Institute of Mental Health grant, National Institute of Neurological Disorders and Stroke grants and a National Cancer Institute grant.

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Correspondence to Jia Zhou.

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DATABASES

Entrez Gene

GCPII

GCPIII

mGlu2

mGlu3

SOD1

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

epilepsy

Huntington's disease

multiple sclerosis

Parkinson's disease

prostate cancer

schizophrenia

stroke

FURTHER INFORMATION

ALS Association

American Stroke Association

Glossary

NEUROPROTECTIVE

An agent that reduces nerve cell death, particularly that resulting from excess glutamate release.

ISCHAEMIA

Loss of blood flow to a tissue; in this review we primarily consider loss of blood flow to the nervous system.

IONOTROPIC

Receptors that are also ion channels.

METABOTROPIC

Receptors that are not ion channels but rather are coupled to second-messenger cascades.

GLUTAMATERGIC

Neurons using glutamate as one of their neurotransmitters.

HYPERALGESIA

An increase in pain perception above the normal response to a stimulus.

PSYCHOMIMETIC

An agent that induces a psychotic-like state.

NEURITE

An extension of a nerve cell that is used to communicate information back to the body of the cell.

SUPEROXIDE DISMUTASE

An enzyme that mediates the conversion of toxic superoxide radicals to peroxide and then to oxygen and water.

PROSTASCINT

A monoclonal antibody to the prostate-specific membrane antigen labeled with indium-111 for the detection of prostate cancer.

POSITRON-EMISSION TOMOGRAPHY

A noninvasive, molecular imaging technique of high sensitivity that detects species labelled with positron-emitting radionuclides in vivo.

DRUGGABILITY

The suitability of a lead candidate that has the requisite physico-chemical/absorption, distribution, metabolism and excretion properties for development as a drug candidate.

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Zhou, J., Neale, J., Pomper, M. et al. NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat Rev Drug Discov 4, 1015–1026 (2005). https://doi.org/10.1038/nrd1903

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