Development of an in vitro screening platform for the identification of partial PPARγ agonists as a source for antidiabetic lead compounds

Lars Porskjær Christensen, Rime El-Houri

Publikation: Bidrag til tidsskriftReviewForskningpeer review

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Resumé

Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.
OriginalsprogEngelsk
TidsskriftMolecules
Vol/bind23
Udgave nummer10
Sider (fra-til)2431
ISSN1420-3049
DOI
StatusUdgivet - 22. sep. 2018

Fingeraftryk

Lead compounds
lead compounds
Peroxisome Proliferator-Activated Receptors
Hypoglycemic Agents
Screening
screening
platforms
glucose
insulin
Glucose
Insulin
Medical problems
Adipocytes
genes
Type 2 Diabetes Mellitus
Insulin Resistance
drugs
hyperglycemia
lipid metabolism
Genes

Citer dette

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Development of an in vitro screening platform for the identification of partial PPARγ agonists as a source for antidiabetic lead compounds. / Christensen, Lars Porskjær ; El-Houri, Rime.

I: Molecules, Bind 23, Nr. 10, 22.09.2018, s. 2431.

Publikation: Bidrag til tidsskriftReviewForskningpeer review

TY - JOUR

T1 - Development of an in vitro screening platform for the identification of partial PPARγ agonists as a source for antidiabetic lead compounds

AU - Christensen, Lars Porskjær

AU - El-Houri, Rime

PY - 2018/9/22

Y1 - 2018/9/22

N2 - Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.

AB - Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.

KW - PPARγ transactivation

KW - adipocyte differentiation

KW - adipocytes

KW - glucose uptake

KW - in silico

KW - insulin

KW - partial PPARγ agonists

KW - plant extracts.

KW - screening platform

KW - type 2 diabetes

KW - Cell Differentiation/drug effects

KW - Humans

KW - PPAR gamma/agonists

KW - Lipid Metabolism/drug effects

KW - Thiazolidinediones/chemistry

KW - Adipocytes/cytology

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Computer Simulation

KW - Drug Evaluation, Preclinical/methods

KW - Hypoglycemic Agents/chemistry

KW - Molecular Docking Simulation

KW - In Vitro Techniques

KW - Gene Expression Regulation/drug effects

U2 - 10.3390/molecules23102431

DO - 10.3390/molecules23102431

M3 - Review

VL - 23

SP - 2431

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 10

ER -