Johns Hopkins Drug Discovery - Project - Glutamate Carboxypeptidase II
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Glutamate Carboxypeptidase II

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Glutamate carboxypeptidase II (GCPII) is a 94 kD class II membrane bound zinc metalloenzyme which catalyzes the hydrolysis of N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartate.  Several decades of pre-clinical work by over a dozen of laboratories have confirmed the potential of GCPII as a pharmacological target in  neurological  diseases wherein excess glutamate is presumed pathogenic, such as stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS), epilepsy, neuropathic pain, chemotherapy-induced neuropathy, schizophrenia, and cognition in multiple sclerosis (1-11). Our laboratory has over two decades of research experience in GCPII inhibitor design and characterization, with 75+ manuscripts and 30+ patents.  While known GCPII inhibitors are potent and selective, as a class they suffer poor physicochemical properties, are ionized at physiological pH, and lack oral bioavailability and brain penetration(12), necessitating extremely large peripheral doses to show efficacy. We are currently developing prodrugs of the most potent phosphonic acid and hydroxamate-based GCPII inhibitors to cover the charged functional group with enhanced gut and tissue penetration. Currently, the lead prodrugs show >100-fold enhancement of oral bioavailability in both rodents and dogs. Non provisional application on these new prodrugs have been filed.

 

In addition to neurological disorders, recent genomic, clinical, and pharmacological data implicate GCPII (also known as Prostate Specific Membrane Antigen; PSMA), in the etiology of inflammatory bowel disease (IBD) (13). We have demonstrated robust 300-1,000% increase in GCPII activity in the intestinal mucosa of patients with active IBD, and inhibitors delivered systemically ameliorate IBD symptoms in several well validated preclinical models (DSS, TNBS, IL-10 KO).  Currently, we are evaluating orally available prodrugs in IBD models. Provisional patent applications covering broad use and composition of matter claiming GCPII inhibition as novel therapeutic approach for IBD have been filed.

 

REFERENCES

1. Ghadge, G.D., et al., Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models. Proceedings of the National Academy of Sciences of the United States of America, 2003. 100(16): p. 9554-9. [PubMed]

2. Carozzi, V.A., et al., Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. Neurotoxicity research, 2010. 17(4): p. 380-91. [PubMed]

3. Rahn, K.A., et al., Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 2012. 109(49): p. 20101-6. [PubMed]

4. Olszewski, R.T., et al., NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. Journal of neurochemistry, 2004. 89(4): p. 876-85. [PubMed]

5. Neale, J.H., et al., The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia. Trends Pharmacol Sci, 2005. 26(9): p. 477-84. [PubMed]

6. Thomas, A.G., et al., Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy. Adv Exp Med Biol, 2006. 576: p. 327-37; discussion 361-3. [PubMed]

7. Slusher, B.S., et al., Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat Med, 1999. 5(12): p. 1396-402. [PubMed]

8. Witkin, J.M., et al., NAALADase (GCP II) inhibition prevents cocaine-kindled seizures. Neuropharmacology, 2002. 43(3): p. 348-56. [PubMed]

9. Zhou, J., et al., NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat Rev Drug Discov, 2005. 4(12): p. 1015-26. [PubMed]

10. Chen, C.H., et al., Genetic influences on cortical regionalization in the human brain. Neuron, 2011. 72(4): p. 537-44. [PubMed]

11. Barinka, C., et al., Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer. Curr Med Chem, 2012. 19(6): p. 856-70. [PubMed]

12. Rais, R., et al., Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA). J Pharm Biomed Anal, 2014. 88: p. 162-9. [PubMed]

13. Zhang, T., et al., An ileal Crohn’s disease gene signature based on whole human genome expression profiles of disease unaffected ileal mucosal biopsies. PLoS One, 2012. 7(5): p. e37139. [PubMed].

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