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Design of Novel PPAR Agonist for Neurodegenerative Disease

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Nuclear Receptors

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Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily comprising three subtypes: PPARα, PPARγ, and PPARβ/δ. The PPAR family of nuclear receptors is centrally involved in regulating whole-body energy homeostasis and metabolic function. Endogenous ligands include free fatty acids, eicosanoids, and leukotrienes. Synthetic ligands developed to serve as full agonists aim at treating diabetes type 2, hyperlipidemia, and other metabolic-related diseases. Further, there has been a developing interest in the role of PPAR agonist’s role in neurodegenerative disease. However, many of these clinically practical therapeutics are associated with harmful effects on human health. Therefore, new approaches have led to a new class of selective PPAR modulators (SPARMs), or partial agonists meet this challenge. In addition, these partial agonists have been observed to show a favorable impact on insulin sensitivity, blood glucose levels, and dyslipidemia with significantly reduced side effects on human health. Partial agonists have been found to display differences in transcriptional and cellular outcomes by acting through distinct structural and dynamic mechanisms within the ligand-binding region when compared to full agonists. Recently, a new focus on PPAR agonists’ class has intensified for neurodegenerative diseases, as new ligands and novel biological roles have emerged particularly for its therapeutic potential in Alzheimer’s disease (AD). The present chapter critically analyzes current PPAR ligands using in silico modeling and the implication of promising new therapeutics in neurodegenerative disorders.

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  1. Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA

    Ian Steinke & Rajesh Amin

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  1. Ian Steinke
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  1. School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

    Mostafa Z. Badr

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Steinke, I., Amin, R. (2021). Design of Novel PPAR Agonist for Neurodegenerative Disease. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_10

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