5y7x | pdb_00005y7x
Human Peroxisome proliferator-activated receptor (PPAR) delta in complexed with a potent and selective agonist
Structural highlights
FunctionPPARD_HUMAN Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.[1] [2] Publication Abstract from PubMedRationale: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by neurotoxicity, excessive inflammation, and cognitive impairment. The peroxisome proliferator-activated receptor (PPAR) delta is a potential target for AD. However, its regulatory mechanisms and therapeutic potential in AD remain unclear. We aimed to investigate if the activation of PPARdelta using a highly selective and potent agonist could provide an effective therapeutic strategy against AD. Methods: We synthesized a novel PPARdelta agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARdelta. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a, the most potent and selective PPARdelta agonist, was confirmed to bind hPPARdelta in a complex by X-ray crystallographic analysis. PPARdelta activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a inhibited amyloid plaque deposition by suppressing the expression of neuronal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and reduced abnormal glial hyperactivation and inflammatory responses, resulting in improved learning and memory in the APP/PS1 mouse model of AD. Conclusion: We identified that specific activation of PPARdelta provides therapeutic effects on multiple pathogenic phenotypes of AD, including neuroinflammation and amyloid deposition. Our findings suggest the potential of PPARdelta as a promising drug target for treating AD. Highly potent and selective PPARdelta agonist reverses memory deficits in mouse models of Alzheimer's disease.,Kim HJ, Kim H, Song J, Hong JY, Lee EH, Londhe AM, Choi JW, Park SJ, Oh E, Yoon H, Hwang H, Hahn D, Jung K, Kwon S, Kadayat TM, Ma MJ, Joo J, Kim J, Bae JH, Hwang H, Pae AN, Cho SJ, Park JH, Chin J, Kang H, Park KD Theranostics. 2024 Sep 16;14(16):6088-6108. doi: 10.7150/thno.96707. eCollection , 2024. PMID:39431021[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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