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TitleCholesterol reduction by immunization with a PCSK9 mimic.
Journal, issue, pagesCell Rep, Vol. 43, Issue 6, Page 114285, Year 2024
Publish dateJun 25, 2024
AuthorsBaoshan Zhang / Gwo-Yu Chuang / Andrea Biju / Daniel Biner / Jiaxuan Cheng / Yiran Wang / Saran Bao / Cara W Chao / Haotian Lei / Tracy Liu / Alexandra F Nazzari / Yongping Yang / Tongqing Zhou / Steven J Chen / Xuejun Chen / Wing-Pui Kong / Li Ou / Danealle K Parchment / Edward K Sarfo / HaoMin SiMa / John-Paul Todd / Shuishu Wang / Ruth A Woodward / Cheng Cheng / Reda Rawi / John R Mascola / Peter D Kwong /
PubMed AbstractProprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue ...Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination.
External linksCell Rep / PubMed:38819987
MethodsEM (single particle)
Resolution5.48 Å
Structure data

EMDB-41409: Cryo-EM structure of PCSK9 mimic HIT01-K21Q-R218E with AMG145 Fab
Method: EM (single particle) / Resolution: 5.48 Å

Source
  • Homo sapiens (human)

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