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 the abundant neuropeptide N-acetylaspartylglutamate (NAAG) to glutamate. GCPII is a well-established therapeutic target in  neurological  diseases wherein excess glutamate is presumed pathogenic1, such as stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS), epilepsy, neuropathic pain, chemotherapy-induced neuropathy, schizophrenia, and cognition in multiple sclerosis2-12. While known GCPII inhibitors are potent and selective, they suffer poor physicochemical properties, are ionized at physiological pH, and lack oral bioavailability and brain penetration13, necessitating large peripheral doses or direct brain injection to exhibit efficacy. Our laboratory has recently developed novel prodrugs of GCPII inhibitors14 that cover their charged functional groups resulting in enhanced oral bioavailability and tissue penetration in both rodents and dogs.

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)15. 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 models16-17.  Currently, we have partnered with a biopharma company to develop orally available GCPII inhibitors in IBD models.  Patent applications covering broad use and composition of matter claiming GCPII inhibition as novel therapeutic approach for IBD have been filed.

Our laboratory has over two decades of experience in GCPII inhibitor design and characterization, with 100+ manuscripts and 30+ patents.

REFERENCES

  1. Vornov, J. J.; Hollinger, K. R.; Jackson, P. F.; Wozniak, K. M.; Farah, M. H.; Majer, P.; Rais, R.; Slusher, B. S., Still NAAG’ing After All These Years: The Continuing Pursuit of GCPII Inhibitors. Adv Pharmacol 2016, 76, 215-55.
  2. Ghadge, G. D.; Slusher, B. S.; Bodner, A.; Canto, M. D.; Wozniak, K.; Thomas, A. G.; Rojas, C.; Tsukamoto, T.; Majer, P.; Miller, R. J.; Monti, A. L.; Roos, R. P., 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), 9554-9.
  3. Carozzi, V. A.; Chiorazzi, A.; Canta, A.; Lapidus, R. G.; Slusher, B. S.; Wozniak, K. M.; Cavaletti, G., Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. Neurotoxicity research 2010, 17 (4), 380-91.
  4. Rahn, K. A.; Watkins, C. C.; Alt, J.; Rais, R.; Stathis, M.; Grishkan, I.; Crainiceau, C. M.; Pomper, M. G.; Rojas, C.; Pletnikov, M. V.; Calabresi, P. A.; Brandt, J.; Barker, P. B.; Slusher, B. S.; Kaplin, A. I., 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), 20101-6.
  5. Olszewski, R. T.; Bukhari, N.; Zhou, J.; Kozikowski, A. P.; Wroblewski, J. T.; Shamimi-Noori, S.; Wroblewska, B.; Bzdega, T.; Vicini, S.; Barton, F. B.; Neale, J. H., 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), 876-85.
  6. Neale, J. H.; Olszewski, R. T.; Gehl, L. M.; Wroblewska, B.; Bzdega, T., The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia. Trends Pharmacol Sci 2005, 26 (9), 477-84.
  7. Thomas, A. G.; Wozniak, K. M.; Tsukamoto, T.; Calvin, D.; Wu, Y.; Rojas, C.; Vornov, J.; Slusher, B. S., Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy. Adv Exp Med Biol 2006, 576, 327-37; discussion 361-3.
  8. Slusher, B. S.; Vornov, J. J.; Thomas, A. G.; Hurn, P. D.; Harukuni, I.; Bhardwaj, A.; Traystman, R. J.; Robinson, M. B.; Britton, P.; Lu, X. C.; Tortella, F. C.; Wozniak, K. M.; Yudkoff, M.; Potter, B. M.; Jackson, P. F., Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat Med 1999, 5 (12), 1396-402.
  9. Witkin, J. M.; Gasior, M.; Schad, C.; Zapata, A.; Shippenberg, T.; Hartman, T.; Slusher, B. S., NAALADase (GCP II) inhibition prevents cocaine-kindled seizures. Neuropharmacology 2002, 43 (3), 348-56.
  10. Zhou, J.; Neale, J. H.; Pomper, M. G.; Kozikowski, A. P., NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat Rev Drug Discov 2005, 4 (12), 1015-26.
  11. Chen, C. H.; Panizzon, M. S.; Eyler, L. T.; Jernigan, T. L.; Thompson, W.; Fennema-Notestine, C.; Jak, A. J.; Neale, M. C.; Franz, C. E.; Hamza, S.; Lyons, M. J.; Grant, M. D.; Fischl, B.; Seidman, L. J.; Tsuang, M. T.; Kremen, W. S.; Dale, A. M., Genetic influences on cortical regionalization in the human brain. Neuron 2011, 72 (4), 537-44.
  12. Barinka, C.; Rojas, C.; Slusher, B.; Pomper, M., Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer. Curr Med Chem 2012, 19 (6), 856-70.
  13. Rais, R.; Rojas, C.; Wozniak, K.; Wu, Y.; Zhao, M.; Tsukamoto, T.; Rudek, M. A.; Slusher, B. S., Bioanalytical method for evaluating the pharmacokinetics of the GCP-II inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA). Journal of pharmaceutical and biomedical analysis 2014, 88, 162-9.
  14. Majer, P.; Jancarik, A.; Krecmerova, M.; Tichy, T.; Tenora, L.; Wozniak, K.; Wu, Y.; Pommier, E.; Ferraris, D.; Rais, R.; Slusher, B. S., Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA). J Med Chem 2016, 59 (6), 2810-9.
  15. Zhang, T.; Song, B.; Zhu, W.; Xu, X.; Gong, Q. Q.; Morando, C.; Dassopoulos, T.; Newberry, R. D.; Hunt, S. R.; Li, E., 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), e37139.
  16. Rais, R.; Jiang, W.; Zhai, H.; Wozniak, K. M.; Stathis, M.; Hollinger, K. R.; Thomas, A. G.; Rojas, C.; Vornov, J. J.; Marohn, M.; Li, X.; Slusher, B. S., FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities. JCI Insight 2016, 1 (12).
  17. Date, A. A.; Rais, R.; Babu, T.; Ortiz, J.; Kanvinde, P.; Thomas, A. G.; Zimmermann, S. C.; Gadiano, A. J.; Halpert, G.; Slusher, B. S.; Ensign, L. M., Local enema treatment to inhibit FOLH1/GCPII as a novel therapy for inflammatory bowel disease. J Control Release 2017.
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