Počet záznamů: 1
A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis
- 1.
SYSNO ASEP 0574388 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis Tvůrce(i) Peters, D. E. (US)
Norris, L. D. (US)
Tenora, Lukáš (UOCHB-X) ORCID
Šnajdr, Ivan (UOCHB-X) ORCID
Ponti, A. K. (US)
Zhu, X. (US)
Sakamoto, S. (US)
Veeravalli, V. (US)
Pradhan, M. (US)
Alt, J. (US)
Thomas, A. G. (US)
Majer, Pavel (UOCHB-X)
Rais, R. (US)
McDonald, C. (US)
Slusher, B. S. (US)Číslo článku eabn7491 Zdroj.dok. Science Translational Medicine. - : American Association for the Advancement of Science - ISSN 1946-6234
Roč. 15, č. 708 (2023)Poč.str. 16 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova gene expression profiles ; dextran sulfate sodium ; membrane antigen PSMA Obor OECD Medicinal chemistry CEP LM2018133 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Způsob publikování Omezený přístup Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 001045323500001 EID SCOPUS 85167529918 DOI 10.1126/scitranslmed.abn7491 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2024 Elektronická adresa https://doi.org/10.1126/scitranslmed.abn7491
Počet záznamů: 1