Rational molecular design of novel class-III peptidic antagonists to competitively disrupt human PPARδ self-binding peptide.

Human peroxisome proliferator-activated receptor-δ (PPARδ) belongs to the nuclear receptor PPAR family that plays central roles in the regulation of glucose and lipid homeostasis and has also been implicated in cell proliferation, differentiation and inflammation. The PPARδ has a ligand-dependent transactivation function module located in the C-terminal helix 12 (H12) of its ligand-binding domain (LBD), which regulates the protein activation and inactivation by dynamically binding to and unbound from the H12-binding site (HBS) of PPARδ LBD domain, thus rendering the H12 as a so-called self-binding peptide (SBP). Currently, the existing PPARδ antagonists can be divided into two classes I and II in terms of their regulatory mechanism; the class-I antagonists competitively block natural agonists, while the class-II antagonists lock H12 out of the HBS site. In this study, class-III PPARδ antagonists were described, which directly target the HBS site and competitively disrupt the activation conformation of H12 in bound form. A self-inhibitory peptide termed HY12 with significant intrinstic disorder was derived from the H12 helical region, and we employed hydrocarbon stapling to constrain the HY12 peptide into a native-like, partially ordered helical conformation. It is confirmed that the stapling can effectively improve the peptide competition potency with native SBP for HBS site. The stapled peptides were considered as promising lead entities and can be used as the start to further develop the class-III peptidic antagonists of PPARδ.