Marine Natural and Nature-Inspired Compounds Targeting Peroxisome Proliferator Activated Receptors (PPARs)

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.

Keywords: PPAR modulators; PPARs; drug discovery; marine natural products.

Figure 1

Schematic representation of PPAR domain organization and PPAR-RXR heterodimer activation. (A) A/B domain (N-terminal variable domain with transactivating AF-1 domain), C (DBD, which contains two Zinc finger (Znf) motifs), D domain (a linker domain), E/F domain (LBD plus transactivating AF-2 domain). (B–E) Schematic representation of PPAR/RXR permissive heterodimers and different ways it can be activated by ligands of either PPAR (C), RXR (D) or by both resulting in a synergistic activation (E) as shown by the increased size of the green arrow. Red circles represent PPAR ligands, green circles RXR ligands.

Figure 2

Representative X-ray complexes of PPAR LBDs. (A): Full view of PPARα LBD (tan) with the full agonist fenofibrate (purple sticks), PDB id: 6LX4. (B): Detail of the ligand binding site of PPARδ LBD (gray) with the full agonist GW501516 (steel blue sticks), PDB id: 5U46. (C): Detail of the ligand binding site of PPARγ LBD (rosy brown) with the full agonist rosiglitazone (magenta sticks), PDB id: 5YCP. Protein sidechains within 4 Å from the ligand are shown in stick representation. Oxygen, nitrogen, and sulfur atoms are colored in red, blue, and yellow, respectively. Direct and water-mediated H-bonds engaged by the ligands are shown as green lines.

Figure 3

2D structures of oxygenated/unsaturated fatty acids and mero/nor-terpenoids discussed in Section 3.1 and Section 3.2.

Figure 4

2D structures of polyketides, lactones, and phtalides discussed in Section 3.3 and Section 3.4.

Figure 5

X-ray structure of PPARγ LBD (colored in light-blue) with the partial agonist butyrolactone I (represented in stick and colored in pink), PDB id: 6L89 (chain B). Protein sidechains within 4 Å from the ligand are shown in stick representation. Oxygen, nitrogen, and sulfur atoms are colored in red, blue, and yellow, respectively. Direct and water-mediated H-bonds engaged by the ligands are shown in wire green.

Figure 6

2D structures of phosphonates and miscellaneous compounds discussed in Section 3.4 and Section 3.5.