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High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice.

ABSTRACT: G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic ? cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents.

SUBMITTER: Zhang M

PROVIDER: S-EPMC3660563 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice.

Zhang Meng M Feng Yang Y Wang Jia J Zhao Jianwei J Li Ting T He Min M Yang Dehua D Nosjean Olivier O Boutin Jean J Renard Pierre P Wang Ming-Wei MW

PloS one 20130521 5

G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simul ...[more]

PMID: 23704946

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Project description:BACKGROUND: Previous studies from our laboratory and others have demonstrated that in addition to altering chromatin acetylation and conformation, histone deacetylase inhibitors (HDACi) disrupt the acetylation status of numerous transcription factors and other proteins. A whole genome yeast deletion library screen was used to identify components of the transcriptional apparatus that modulate the sensitivity to the hydroxamic acid-based HDACi, CG-1521. RESULTS: Screening 4852 haploid Saccharomyces cerevisiae deletion strains for sensitivity to CG-1521 identifies 407 sensitive and 80 resistant strains. Gene ontology (GO) enrichment analysis shows that strains sensitive to CG-1521 are highly enriched in processes regulating chromatin remodeling and transcription as well as other ontologies, including vacuolar acidification and vesicle-mediated transport. CG-1521-resistant strains include those deficient in the regulation of transcription and tRNA modification. Components of the SAGA histone acetyltransferase (HAT) complex are overrepresented in the sensitive strains, including the catalytic subunit, Gcn5. Cell cycle analysis indicates that both the wild-type and gcn5? strains show a G1 delay after CG-1521 treatment, however the gcn5? strain displays increased sensitivity to CG-1521-induced cell death compared to the wild-type strain. To test whether the enzymatic activity of Gcn5 is necessary in the response to CG-1521, growth assays with a yeast strain expressing a catalytically inactive variant of the Gcn5 protein were performed and the results show that this strain is less sensitive to CG-1521 than the gcn5? strain. CONCLUSION: Genome-wide deletion mutant screening identifies biological processes that affect the sensitivity to the HDAC inhibitor CG-1521, including transcription and chromatin remodeling. This study illuminates the pathways involved in the response to CG-1521 in yeast and provides incentives to understand the mechanisms of HDAC inhibitors in cancer cells. The data presented here demonstrate that components of the SAGA complex are involved in mediating the response to CG-1521. Additional experiments suggest that functions other than the acetyltransferase activity of Gcn5 may be sufficient to attenuate the effects of CG-1521 on cell growth.

Project description:Medicinal plants containing complex mixtures of several compounds with various potential beneficial biological effects are attractive treatment interventions for a complex multi-faceted disease like diabetes. In this study, compounds identified from African medicinal plants were evaluated for their potential anti-diabetic activity. A total of 867 compounds identified from over 300 medicinal plants were screened in silico with the DIA-DB web server (http://bio-hpc.eu/software/dia-db/) against 17 known anti-diabetic drug targets. Four hundred and thirty compounds were identified as potential inhibitors, with 184 plants being identified as the sources of these compounds. The plants Argemone ochroleuca, Clivia miniata, Crinum bulbispermum, Danais fragans, Dioscorea dregeana, Dodonaea angustifolia, Eucomis autumnalis, Gnidia kraussiana, Melianthus comosus, Mondia whitei, Pelargonium sidoides, Typha capensis, Vinca minor, Voacanga Africana, and Xysmalobium undulatum were identified as new sources rich in compounds with a potential anti-diabetic activity. The major targets identified for the natural compounds were aldose reductase, hydroxysteroid 11-beta dehydrogenase 1, dipeptidyl peptidase 4, and peroxisome proliferator-activated receptor delta. More than 30% of the compounds had five or more potential targets. A hierarchical clustering analysis coupled with a maximum common substructure analysis revealed the importance of the flavonoid backbone for predicting potential activity against aldose reductase and hydroxysteroid 11-beta dehydrogenase 1. Filtering with physiochemical and the absorption, distribution, metabolism, excretion and toxicity (ADMET) descriptors identified 28 compounds with favorable ADMET properties. The six compounds-crotofoline A, erythraline, henningsiine, nauclefidine, vinburnine, and voaphylline-were identified as novel potential multi-targeted anti-diabetic compounds, with favorable ADMET properties for further drug development.

Dataset Information

High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice.

Publications

High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice.

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