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The PPAR ? Pocket: Renewed Opportunities for Drug Development.

ABSTRACT: The past decade of PPAR? research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPAR? ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPAR? ligands, capable of isolating central therapeutic effects of PPAR? modulation, while displaying markedly lower toxicities than previous generations of PPAR? ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPAR? and PPAR?/?. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the ? pockets of PPAR? and PPAR?/?. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPAR? and PPAR?/?. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

SUBMITTER: Kaupang A

PROVIDER: S-EPMC7351019 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The PPAR Ω Pocket: Renewed Opportunities for Drug Development.

Kaupang Åsmund Å Hansen Trond Vidar TV

PPAR research 20200701

The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ lig ...[more]

PMID: 32695150

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Project description:Peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPAR? are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPAR? signaling and to develop safer and more effective PPAR?-directed therapeutics. In addition to PPAR? itself, many PPAR? ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPAR? responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPAR? genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPAR? co-activator-1?, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPAR?-dependent transcription. Therefore in endothelium, GPR40 and PPAR? function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPAR?. Thus the role of GPR40 in PPAR? signaling may have important implications for drug development. Ligands that strongly activate PPAR?, but do not bind to or activate GPR40 may be safer than currently approved PPAR? agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPAR?, but not ERK1/2, avoiding its harmful effects on PPAR? signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.

Dataset Information

The PPAR ? Pocket: Renewed Opportunities for Drug Development.

Publications

The PPAR <i>Ω</i> Pocket: Renewed Opportunities for Drug Development.

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