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

Animals Humans Mice Colitis / drug therapy Colon / pathology Cytokines / metabolism Disease Models, Animal Glutamate Carboxypeptidase II / antagonists & inhibitors Inflammation / pathology Inflammatory Bowel Diseases / drug therapy Mice, Inbred C57BL

Journal

Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086

Informations de publication

Date de publication:
09 08 2023
Historique:
medline: 11 8 2023
pubmed: 9 8 2023
entrez: 9 8 2023
Statut: ppublish

Résumé

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, (

Identifiants

DOI: 10.1126/scitranslmed.abn7491 PMID: 37556558 PMC: PMC10661206
pubmed: 37556558
doi: 10.1126/scitranslmed.abn7491
pmc: PMC10661206
mid: NIHMS1944692
doi:

Substances chimiques

Cytokines 0
Glutamate Carboxypeptidase II EC 3.4.17.21

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

eabn7491

Subventions

Organisme : NCCIH NIH HHS
ID : K01 AT010984
Pays : United States
Organisme : NIH HHS
ID : K01 OD030517
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM143298
Pays : United States
Organisme : NIH HHS
ID : T32 OD011089
Pays : United States

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Auteurs

Diane E Peters (DE)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0003-4185-6203

Lauren D Norris (LD)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Lukáš Tenora (L)

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 160 00 Prague, Czechia.
ORCID: 0000-0002-6982-3545

Ivan Šnajdr (I)

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 160 00 Prague, Czechia.
ORCID: 0000-0002-0831-4034

András K Ponti (AK)

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
ORCID: 0000-0001-8696-5038

Xiaolei Zhu (X)

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0003-2733-242X

Shinji Sakamoto (S)

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0001-5498-551X

Vijayabhaskar Veeravalli (V)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Manisha Pradhan (M)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0002-8710-0148

Jesse Alt (J)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0001-5440-7891

Ajit G Thomas (AG)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0001-5922-5050

Pavel Majer (P)

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 160 00 Prague, Czechia.
ORCID: 0000-0002-1804-6934

Rana Rais (R)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0003-4059-2453

Christine McDonald (C)

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
ORCID: 0000-0002-6745-9487

Barbara S Slusher (BS)

Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
ORCID: 0000-0001-9814-4157

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du côlon › Colite › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Système digestif › Tube digestif › Tube digestif inférieur › Gros intestin › Côlon › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Metalloproteases › Metalloexopeptidases › Glutamate carboxypeptidase II › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies inflammatoires intestinales › A gut-restricted glutamate carboxypeptidase II...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › A gut-restricted glutamate carboxypeptidase II...