Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)
Enrico D'Aniello1, Pietro Amodeo2, Rosa Maria Vitale2
1Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy.
Abstract:
Peroxisome proliferator-activated receptors α, γ and β/δ (PPARα, PPARγ, and PPARβ/δ) are a family of ligand-activated transcriptional factors belonging to the superfamily of nuclear receptors regulating the expression of genes involved in lipid and carbohydrate metabolism, energy homeostasis, inflammation, and the immune response. For this reason, they represent attractive targets for the treatment of a variety of metabolic diseases and, more recently, for neurodegenerative disorders due to their emerging neuroprotective effects. The degree of activation, from partial to full, along with the selectivity toward the different isoforms, greatly affect the therapeutic efficacy and the safety profile of PPAR agonists. Thus, there is a high interest toward novel scaffolds with proper combinations of activity and selectivity. This review intends to provide an overview of the discovery, optimization, and structure-activity relationship studies on PPAR modulators from marine sources, along with the structural and computational studies that led to their identification and/or elucidation, and rationalization of their mechanisms of action.
Insights
Marine natural products offer promising PPAR modulators for metabolic and neurodegenerative diseases. Research focuses on optimizing their activity and selectivity for improved therapeutic efficacy and safety.
Area of Science:
- Biochemistry
- Pharmacology
- Marine Natural Products Chemistry
Background:
- Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating metabolism, inflammation, and immunity.
- PPARs are therapeutic targets for metabolic diseases and neurodegenerative disorders due to their neuroprotective effects.
- PPAR agonist efficacy and safety depend on activation degree and isoform selectivity.
Purpose of the Study:
- To review the discovery and optimization of PPAR modulators from marine sources.
- To explore structure-activity relationships (SAR) of marine-derived PPAR modulators.
- To summarize structural and computational studies elucidating their mechanisms of action.
Main Methods:
- Literature review of marine natural products targeting PPARs.
- Analysis of structure-activity relationship studies.
- Examination of structural and computational investigations.
Main Results:
- Marine sources yield diverse PPAR modulators with varying activity and selectivity profiles.
- Optimization studies have identified potent and selective PPAR agonists and antagonists.
- Structural and computational analyses provide insights into PPAR-ligand interactions and mechanisms.
Conclusions:
- Marine natural products represent a valuable resource for developing novel PPAR-targeting therapeutics.
- Further research into SAR and mechanisms can guide the design of improved PPAR modulators.
- These compounds hold potential for treating metabolic and neurodegenerative conditions.
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