{"doi":"10.1126/scitranslmed.abn7491","title":"A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis","abstract":"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–α 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.","journal":"Science Translational Medicine","year":2023,"id":329923,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":597970,"name":"Lauren Norris","orcid":null,"position":1,"is_corresponding":false},{"id":228370,"name":"Lukáš Tenora","orcid":"0000-0002-6982-3545","position":2,"is_corresponding":false},{"id":920985,"name":"Ivan Šnajdr","orcid":"0000-0002-0831-4034","position":3,"is_corresponding":false},{"id":994332,"name":"András K. Ponti","orcid":"0000-0001-8696-5038","position":4,"is_corresponding":false},{"id":574426,"name":"Xiaolei Zhu","orcid":"0000-0003-2733-242X","position":5,"is_corresponding":false},{"id":663602,"name":"Shinji Sakamoto","orcid":"0000-0001-5498-551X","position":6,"is_corresponding":false},{"id":356506,"name":"Vijayabhaskar Veeravalli","orcid":"0000-0003-0459-964X","position":7,"is_corresponding":false},{"id":227990,"name":"Manisha Pradhan","orcid":"0000-0002-8710-0148","position":8,"is_corresponding":false},{"id":493907,"name":"Jesse Alt","orcid":"0000-0001-5440-7891","position":9,"is_corresponding":false},{"id":356504,"name":"Ajit G. Thomas","orcid":"0000-0001-5922-5050","position":10,"is_corresponding":false},{"id":228371,"name":"Pavel Majer","orcid":"0000-0002-1804-6934","position":11,"is_corresponding":false},{"id":228372,"name":"Rana Rais","orcid":"0000-0003-4059-2453","position":12,"is_corresponding":false},{"id":302610,"name":"Christine McDonald","orcid":"0000-0002-6745-9487","position":13,"is_corresponding":false},{"id":228373,"name":"Barbara S. Slusher","orcid":"0000-0001-9814-4157","position":14,"is_corresponding":false},{"id":1053124,"name":"Diane E. Peters","orcid":"0000-0003-4185-6203","position":0,"is_corresponding":true}],"reference_count":104,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:05.843139Z","pmid":"37556558","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}