Abstract 405: Short Stapled ApoC-II Mimetic Peptides Activate Lipoprotein Lipase And Decrease Plasma Triglycerides In Mouse Models

Abstract

The metabolism of triglyceride-rich lipoproteins plays an important role in cardiovascular diseases and dyslipidemias. Lowering plasma triglycerides (TGs) by activating lipoprotein lipase (LPL), the main plasma enzyme that hydrolyses TGs, with ApoC-II mimetic peptides is a potential strategy for treatment of ApoC-II deficiency, potentially other forms of hypertriglyceridemia.We previously described a dual ApoC-II mimetic/ApoC-III antagonist peptide called D6-PV. It’s a bihelical, 41 amino acid long peptide with the first helix designed to bind to lipoproteins and the second helix to activate LPL. D6-PV showed a marked reduction in plasma TGs in ApoC-II Knock-Out and ApoC-III transgenic mouse models.We employed a hydrocarbon stapling technique to make a new single helix SP1 peptide based on the last 21 C-terminal amino acids (A59-E79) of ApoC-II. The staple increased the peptide’s ability to bind to lipoproteins and improved amphipathicity without interfering with the lipoprotein lipase activating motif located on the hydrophilic face of the peptide.The SP1 peptide was more potent than D6-PV in its ability to increase LPL activity in vitro . Intraperitoneal injection of the SP1 peptide into ApoC-II Knock-Out or ApoC-III transgenic mice (1-5 umole/kg) showed similar to the D6-PV a 70-90 percent reduction in plasma triglycerides 1 hour after injection.We also used two consecutive staples or “stitching” to make the SP2 peptide. These modifications along with Glycine77 to N -methyl-glycine substitution and replacing two C-terminal Glutamic acids with their D-isomer analogs made the SP2 peptide resistant to proteolysis by trypsin, pepsin and Proteinase K.In summary, the new SP1 and SP2 peptides could be a treatment for chronic or acute hypertriglyceridemia, acute pancreatitis and a potential oral therapy for ApoC-II deficiency.