A Therapeutic Peptide Vaccine Against PCSK9

• DOI: 10.1038/s41598-017-13069-w
• Publication Date: 2017-09-26T13:31:14Z
• Authors: Yajie Pan; Yanzhao Zhou; Hailang Wu; Xiao Chen; Xiajun Hu; Hongrong Zhang; Zihua Zhou; Zhihua Qiu; Yuhua Liao
• Keywords: Mice, Knockout; 0303 health sciences; Hypercholesterolemia; PCSK9 Inhibitors; Article; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Cholesterol; Immunogenicity, Vaccine; Gene Expression Regulation; Receptors, LDL; Catalytic Domain; Immunoglobulin G; Mutation; Vaccines, Subunit; Phosphoprotein Phosphatases; Animals; Humans; Hepatocyte Nuclear Factor 1-alpha; Proprotein Convertase 9; Hydrophobic and Hydrophilic Interactions; Sterol Regulatory Element Binding Protein 2

AbstractVaccination provides a promising approach for treatment of hypercholesterolemia and improvement in compliance. In this study, the appropriate virus-like particle (VLP)-peptide vaccines targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) were screened. The screening criteria of target peptides were as follows: (1) located in catalytic domain of PCSK9, or regulating the binding of PCSK9 and LDL receptors (LDLR); (2) having low/no-similarity when matched with the host proteome; (3) possessing ideal antigenicity and hydrophilicity; (4) including the functional mutation site of PCSK9. It was found that mice vaccinated with VLP -PCSK9 peptide vaccines, especially PCSK9Qβ-003 vaccine, developed high titer IgG antibodies against PCSK9. PCSK9Qβ-003 vaccine obviously decreased plasma total cholesterol in both Balb/c mice and LDLR+/− mice. Also, PCSK9Qβ-003 vaccine decreased plasma PCSK9 level and up-regulated LDLR expression in liver. Additionally, PCSK9Qβ-003 vaccine injection was associated with significant up-regulation of sterol-regulatory element-binding protein-2 (SREBP-2), hepatocyte nuclear factor 1α (HNF-1α), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in LDLR+/− mice. No obvious immune injury was detected in vaccinated animals. The PCSK9Qβ-003 vaccine, therefore, may be an attractive treatment approach for hypercholesterolemia through decreasing cholesterol and regulating lipid homeostasis.