Discovery of undescribed PCSK9 inhibitory activities in Annonaceous acetogenins from Polyalthia evecta

Bioassay-guided isolation using a HepG2 cell-based proprotein convertase subtilisin/kexin type 9 (PCSK9) ELISA led to the isolation of four previously unreported (1-4) and six known (5-10) mono-tetrahydrofuran Annonaceous acetogenins from the branches of Polyalthia evecta. The structures of all isolates were elucidated based on spectroscopic data analyses or chemical reaction including 1D and 2D NMR, HRESIMS, LC-MS/MS of the lithium adducts, ECD measurements and the modified Mosher's method. All isolates were evaluated for their PCSK9 secretion inhibitory activities, and a plausible structure-activity relationship was proposed. Among them, compound 5 (annonacin) significantly suppressed PCSK9 secretion as well as expressions of PCSK9 mRNA and protein. Moreover, this compound 5 enhanced LDL uptake, and mitigated atorvastatin-induced upregulation of PCSK9. This study represents the first investigation for the PCSK9 inhibitory potential of acetogenin-class compounds.