A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis

0574388 - ÚOCHB 2024 RIV US eng J - Journal Article
Peters, D. E. - Norris, L. D. - Tenora, Lukáš - Šnajdr, Ivan - Ponti, A. K. - Zhu, X. - Sakamoto, S. - Veeravalli, V. - Pradhan, M. - Alt, J. - Thomas, A. G. - Majer, Pavel - Rais, R. - McDonald, C. - Slusher, B. S.
A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis.
Science Translational Medicine. Roč. 15, č. 708 (2023), č. článku eabn7491. ISSN 1946-6234. E-ISSN 1946-6242
R&D Projects: GA MŠMT(CZ) LM2018133
Institutional support: RVO:61388963
Keywords : gene expression profiles * dextran sulfate sodium * membrane antigen PSMA
OECD category: Medicinal chemistry
Impact factor: 17.1, year: 2022
Method of publishing: Limited access
https://doi.org/10.1126/scitranslmed.abn7491

There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUC(colon/plasma) > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-a and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.
Permanent Link: https://hdl.handle.net/11104/0344718