Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels

International Journal of Molecular Sciences
Chuantao JiangBa-Bie Teng

Abstract

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe-/- mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe-/- mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe-/- mice. The X-PCSK9-B1 treated mice ha...Continue Reading

References

May 19, 1995·The Journal of Biological Chemistry·J Y ChangB Chatrenet
May 10, 1994·Proceedings of the National Academy of Sciences of the United States of America·S IshibashiM S Brown
May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
Jan 12, 2007·Trends in Biochemical Sciences·Jay D HortonHelen H Hobbs
Nov 21, 2008·Journal of Lipid Research·Jay D HortonHelen H Hobbs
Mar 31, 2009·International Journal of Cardiology·Rabindra PandeySu Li Jie
May 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joyce C Y ChanSimon M Jackson
Nov 26, 2009·International Journal of Cardiology·Fang HongLou Ming
Feb 2, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ashley D ReynoldsHoward E Gendelman
Jun 29, 2010·Journal of the American College of Cardiology·Marianne BennAnne Tybjaerg-Hansen
Nov 21, 2013·Journal of Molecular Biology·Felix SchieleHerbert Nar
Oct 25, 2014·Arteriosclerosis, Thrombosis, and Vascular Biology·Marta Roche-MolinaJuan A Bernal
Mar 17, 2015·The New England Journal of Medicine·Jennifer G RobinsonUNKNOWN ODYSSEY LONG TERM Investigators
Dec 14, 2016·The New England Journal of Medicine·Kevin FitzgeraldAmy Simon
Mar 18, 2017·The New England Journal of Medicine·Marc S SabatineUNKNOWN FOURIER Steering Committee and Investigators
Mar 18, 2017·The New England Journal of Medicine·Paul M RidkerUNKNOWN SPIRE Investigators
Mar 18, 2017·The New England Journal of Medicine·Paul M RidkerUNKNOWN SPIRE Cardiovascular Outcome Investigators
Apr 27, 2017·JAMA : the Journal of the American Medical Association·Stephen J NichollsSteven E Nissen
Aug 17, 2017·The New England Journal of Medicine·Robert P GiuglianoUNKNOWN EBBINGHAUS Investigators
Aug 23, 2017·JAMA : the Journal of the American Medical Association·Dhruv S KaziKirsten Bibbins-Domingo
Sep 1, 2017·Human Vaccines & Immunotherapeutics·Margaret E Gatti-MaysMarijo Bilusic
Nov 25, 2017·Journal of the American College of Cardiology·Mark A Hlatky, Dhruv S Kazi
Nov 29, 2017·Annals of Internal Medicine·Michael D ShapiroSergio Fazio

❮ Previous
Next ❯

Citations

May 14, 2019·BioMed Research International·Rong TangKai-Jiang Yu

❮ Previous
Next ❯

Methods Mentioned

BETA
antisense oligonucleotides
PCR
protein folding
transfection
ELISA
Infrared Imaging

Clinical Trials Mentioned

NCT01663402

Software Mentioned

SAS
GraphPad Prism

Related Concepts

Related Feeds

ApoE, Lipids & Cholesterol

Serum cholesterol, triglycerides, apolipoprotein B (APOB)-containing lipoproteins (very low-density lipoprotein (VLDL), immediate-density lipoprotein (IDL), and low-density lipoprotein (LDL), lipoprotein A (LPA)) and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are all connected in diseases. Here is the latest research.

ApoE Phenotypes

Apolipoprotein E (APOE) is a protein involved in fat metabolism and associated with the pathogenesis of Alzheimer's disease and cardiovascular disease. Here is the latest research on APOE phenotypes.