Main groups of proprotein convertase subtilisin/kexin type 9 inhibitors: mechanisms of action and clinical efficacy. Part 2

DOI: https://doi.org/10.29296/25877305-2021-04-05
Download full text PDF
Issue: 
4
Year: 
2021

A. Chaulin(1, 2), N. Svechkov(1, 2), S. Volkova(1) (1)Samara Regional Cardiology Dispensary,
Samara (2)Samara State Medical University

The proprotein convertase subtilisin-kexin type 9 (PCSK9) is considered a promising therapeutic target for the development of new drug groups aimed at the treatment and prevention of dyslipidemia and cardiovascular diseases (CVD). This article is a continuation of the earlier discussion of the main groups of PCSK9 inhibitors. The article discusses in detail the mechanisms of action and clinical efficacy of the following groups of drugs: low-molecular-weight PCSK9 inhibitors, mimetic peptides, and PCSK9 vaccines.

Keywords: 
cardiology
proprotein convertase subtilisin-kexin type 9
atherosclerosis
cholesterol
low-density lipoproteins
low-density lipoprotein receptors
cardiovascular diseases
PCSK9 inhibitors
mimetic peptides
vaccine



It appears your Web browser is not configured to display PDF files. Download adobe Acrobat или click here to download the PDF file.

References: 
  1. Chaulin A.M., Dupljakov D.V. PCSK-9: sovremennye predstavlenija o biologicheskoj roli i vozmozhnosti ispol'zovanija v kachestve diagnosticheskogo markera serdechno-sosudistyh zabolevanij. Chast' 1. Kardiologija: novosti, mnenija, obuchenie. 2019; 7 (2): 45–57 [Chaulin A.M., Duplyakov D.V. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. Part 1. Kardiologiya: novosti, mneniya, obuchenie = Cardiology: News, Opinions, Training. 2019; 7 (2): 45–57 (in Russ.)]. DOI: 10.24411/2309-1908-2019-12005
  2. Chaulin A.M., Dupljakov D.V. PCSK-9: sovremennye predstavlenija o biologicheskoj roli i vozmozhnosti ispol'zovanija v kachestve diagnosticheskogo markera serdechno-sosudistyh zabolevanij. Chast' 2. Kardiologija: novosti, mnenija, obuchenie. 2019; 7 (4): 24–35 [Chaulin A.M., Duplyakov D.V. PCSK-9: modern views about biological role and possibilities of use as a diagnostic marker for cardiovascular diseases. Part 2. Kardiologiya: novosti, mneniya, obuchenie = Cardiology: News, Opinions, Training. 2019; 7 (4): 24–35 (in Russ.)]. DOI: 10.24411/2309-1908-2019-14004
  3. Tóth Š., Fedačko J., Pekárová T. et al. Elevated Circulating PCSK9 Concentrations Predict Subclinical Atherosclerotic Changes in Low Risk Obese and Non-Obese Patients. Cardiol Ther. 2017; 6 (2): 281–9. DOI: 10.1007/s40119-017-0092-8
  4. Chaulin A.M., Dupljakov D.V. Biomarkery ostrogo infarkta miokarda: diagnosticheskaja i prognosticheskaja tsennost'. Chast' 2 (obzor literatury). Klinicheskaja praktika. 2020; 11 (4): 70–82 [Chaulin A.M., Duplyakov D.V. Biomarkers of Acute Myocardial Infarction: Diagnostic and Prognostic Value. Part 2 (Literature Review). Journal of Clinical Practice. 2020; 11 (4): 70–82 (in Russ.)]. DOI: 10.17816/clinpract48893
  5. Bae K.H., Kim S.W., Choi Y.K. et al. Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome. Diabetes Metab J. 2018; 42 (3): 207–14. DOI: 10.4093/dmj.2017.0081
  6. Chaulin A.M., Dupljakov D.V. Rol' PCSK9 v reguljatsii transporta lipoproteinov (obzor literatury). Voprosy biologicheskoj, meditsinskoj i farmatsevticheskoj himii. 2021; 24 (1): 42–5 [Chaulin A.M., Duplyakov D.V. The role of PCSK9 in the regulation of lipoprotein transport (literature review). Problems of biological, medical and pharmaceutical chemistry. 2021; 24 (1): 42–5 (in Russ.)]. DOI: 10.29296/25877313-2021-01-04
  7. Chaulin A.M., Volkova S.L., Svechkov N.A. Osnovnye gruppy ingibitorov proproteinovoj konvertazy subtilizin-keksinovogo tipa 9 (PCSK9): mehanizmy dejstvija i klinicheskaja effektivnost'. Ch. 1. Vrach. 2021; 32 (3): 21–6 [Chaulin A.M., Volkova S. L., Svechkov N. A. Main groups of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: mechanisms of action and clinical efficacy. Part 1. Vrach. 2021; 2021; 32 (3): 21–6 (in Russ.)]. DOI: 10.29296/25877305-2021-03-04
  8. Lo Surdo P., Bottomley M.J., Calzetta A. et al. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep. 2011; 12: 1300–5. DOI: 10.1038/embor.2011.205
  9. Banerjee Y., Santos R.D., Al-Rasadi K. et al. Targeting PCSK9 for therapeutic gains: Have we addressed all the concerns? Atherosclerosis. 2016; 248: 62–75. DOI: 10.1016/j.atherosclerosis.2016.02.018
  10. Rothe C., Skerra A. Anticalin((R)) proteins as therapeutic agents in human diseases. BioDrugs. 2018; 32: 233–43. DOI: 10.1007/s40259-018-0278-1
  11. Masuda Y., Yamaguchi S., Suzuki C. et al. Generation and characterization of a novel small biologic alternative to proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies, DS-9001a, albumin binding domain-fused anticalin protein. J Pharmacol Exp Ther. 2018; 365: 368–78. DOI: 10.1124/jpet.117.246652
  12. Gebauer M., Skerra A. Anticalins small engineered binding proteins based on the lipocalin scaffold. Methods Enzymol. 2012; 503: 157–88. DOI: 10.1016/B978-0-12-396962-0.00007-0
  13. Seidah N.G., Prat A., Pirillo A. et al. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res. 2019; 115 (3): 510–8. DOI: 10.1093/cvr/cvz003
  14. Inazu A., Brown M.L., Hesler C.B. et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990; 323: 1234–8. DOI: 10.1056/NEJM199011013231803
  15. Miyosawa K., Watanabe Y., Murakami K. et al. New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism. Am J Physiol Endocrinol Metab. 2015; 309: E177–190. DOI: 10.1152/ajpendo.00528.2014
  16. Lintner N.G., McClure K.F., Petersen D. et al. Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol. 2017; 15: e2001882. DOI: 10.1371/journal.pbio.2001882
  17. Mullard A. Nine paths to PCSK9 inhibition. Nat Rev Drug Discov. 2017; 16: 299–301. DOI: 10.1038/nrd.2017.83
  18. Imanshahidi M., Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res. 2008; 22: 999–1012. DOI: 10.1002/ptr.2399
  19. Kong W., Wei J., Abidi P. et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004; 10: 1344–51. DOI: 10.1038/nm1135
  20. Li H., Dong B., Park S.W. et al. Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem. 2009; 284: 28885–95. DOI: 10.1074/jbc.M109.052407
  21. Cameron J., Ranheim T., Kulseth M.A. et al. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis. 2008; 201: 266–73. DOI: 10.1016/j.atherosclerosis.2008.02.004
  22. Sultana N., Ata A. Oleanolic acid and related derivatives as medicinally important compounds. J Enzyme Inhib Med Chem. 2008; 23: 739–56. DOI: 10.1080/14756360701633187
  23. Chen S., Wen X., Zhang W. et al. Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1beta axis in high-fat diet-induced hyperlipidemic mice. FASEB J. 2017; 31: 1085–96. DOI: 10.1096/fj.201601022R
  24. Tsai S.J., Yin M.C. Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells. J Food Sci. 2008; 73: H174–178. DOI: 10.1111/j.1750-3841.2008.00864.x
  25. Wang X., Liu R., Zhang W. et al. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol Cell Endocrinol. 2013; 376: 70–80. DOI: 10.1016/j.mce.2013.06.014
  26. Rodriguez-Rodriguez R., Stankevicius E., Herrera M.D. et al. Oleanolic acid induces relaxation and calcium-independent release of endothelium-derived nitric oxide. Br J Pharmacol. 2008; 155: 535–46. DOI: 10.1038/bjp.2008.289
  27. He N.Y., Li Q., Wu C.Y. et al. Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives. Acta Pharmacol Sin. 2017; 38: 301–11. DOI: 10.1038/aps.2016.134
  28. Zhao Z., Tuakli-Wosornu Y., Lagace T.A. et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006; 79: 514–23. DOI: 10.1086/507488
  29. Gustafsen C., Kjolby M., Nyegaard M. et al. The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion. Cell Metab. 2014; 19: 310–8. DOI: 10.1016/j.cmet.2013.12.006
  30. Hu D., Yang Y., Peng D.Q. Increased sortilin and its independent effect on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in statin-naive patients with coronary artery disease. Int J Cardiol. 2017; 227: 61–5. DOI: 10.1016/j.ijcard.2016.11.064
  31. Goettsch C., Kjolby M., Aikawa E. Sortilin and its multiple roles in cardiovascular and metabolic diseases. Arterioscler Thromb Vasc Biol. 2018; 38: 19–25. DOI: 10.1161/ATVBAHA.117.310292
  32. Nykjaer A., Lee R., Teng K.K. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004; 427: 843–8. DOI: 10.1038/nature02319
  33. Debose-Boyd R.A., Horton J.D. Opening up new fronts in the fight against cholesterol. Elife. 2013; 2: e00663. DOI: 10.7554/eLife.00663
  34. Chen X.W., Wang H., Bajaj K. et al. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. Elife. 2013; 2: e00444. DOI: 10.7554/eLife.00444
  35. Jung C.H., Cho I., Ahn J. et al. Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes. Phytother Res. 2013; 27: 139–43. DOI: 10.1002/ptr.4687
  36. Mbikay M., Mayne J., Sirois F. et al. Mice fed a high-cholesterol diet supplemented with quercetin-3-glucoside show attenuated hyperlipidemia and hyperinsulinemia associated with differential regulation of PCSK9 and LDLR in their liver and pancreas. Mol Nutr Food Res. 2018; 62: e1700729. DOI: 10.1002/mnfr.201700729
  37. Mbikay M., Sirois F., Simoes S. et al. Quercetin-3-glucoside increases low-density lipoprotein receptor (LDLR) expression, attenuates proprotein convertase subtilisin/kexin 9 (PCSK9) secretion, and stimulates LDL uptake by Huh7 human hepatocytes in culture. FEBS Open Biol. 2014; 4: 755–62. DOI: 10.1016/j.fob.2014.08.003
  38. Craik D.J., Fairlie D.P., Liras S. et al. The future of peptide-based drugs. Chem Biol Drug Des. 2013; 81: 136–47. DOI: 10.1111/cbdd.12055
  39. Zhang D.W., Lagace T.A., Garuti R. et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007; 282: 18602–12. DOI: 10.1074/jbc.M702027200
  40. Tveten K., Holla O.L., Cameron J. et al. Interaction between the ligand-binding domain of the LDL receptor and the C-terminal domain of PCSK9 is required for PCSK9 to remain bound to the LDL receptor during endosomal acidification. Hum Mol Genet. 2012; 21: 1402–9. DOI: 10.1093/hmg/ddr578
  41. Schroeder C.I., Swedberg J.E., Withka J.M. et al. Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro. Chem Biol. 2014; 21: 284–94. DOI: 10.1016/j.chembiol.2013.11.014
  42. McNutt M.C., Kwon H.J., Chen C. et al Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem. 2009; 284: 10561–70. DOI: 10.1074/jbc.M808802200
  43. Zhang Y., Eigenbrot C., Zhou L. et al. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem. 2014; 289: 942–55. DOI: 10.1074/jbc.M113.514067
  44. Du F., Hui Y., Zhang M. et al. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem. 2011; 286: 43054–61. DOI: 10.1074/jbc.M111.273474
  45. Alghamdi R.H., O’Reilly P., Lu C. et al. LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153-421): design, synthesis and biochemical evaluation. Eur J Med Chem. 2015; 92: 890–907. DOI: 10.1016/j.ejmech.2015.01.022
  46. Mayer G., Poirier S., Seidah N.G. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J Biol Chem. 2008; 283: 31791–801. DOI: 10.1074/jbc.m805971200
  47. Seidah N.G., Poirier S., Denis M. et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLoS One. 2012; 7: e41865. DOI: 10.1371/journal.pone.0041865
  48. Ly K., Saavedra Y.G., Canuel M. et al. Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9. J Biol Chem. 2014; 289: 17732–46. DOI: 10.1074/jbc.M113.541094
  49. Chackerian B., Remaley A. Vaccine strategies for lowering LDL by immunization against proprotein convertase subtilisin/kexin type 9. Curr Opin Lipidol. 2016; 27: 345–50. DOI: 10.1097/mol.0000000000000312
  50. Landlinger C., Pouwer M.G., Juno C. et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur Heart J. 2017; 38: 2499–507. DOI: 10.1093/eurheartj/ehx260
  51. Galabova G., Brunner S., Winsauer G. et al. Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management. PLoS One. 2014; 9: e114469. DOI: 10.1371/journal.pone.0114469
  52. Crossey E., Amar M.J.A., Sampson M. et al. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. 2015; 33: 5747–55. DOI: 10.1016/j.vaccine.2015.09.044
  53. Civeira F., Jarauta E. Vaccine against PCSK9: the natural strategy from passive to active immunization for the prevention of atherosclerosis. J Thorac Dis. 2017; 9: 4291–4. DOI: 10.21037/jtd.2017.10.18
  54. Chaulin A.M., Mazaev A.Ju., Aleksandrov A.G. Rol' proprotein konvertazy subtilizin/keksin tipa 9 (pcsk-9) v metabolizme holesterina i novye vozmozhnosti lipidkorrigujuschej terapii. Mezhdunarodnyj nauchno-issledovatel'skij zhurnal. 2019; 4–1 (82): 124–6 [Chaulin A.M., Mazaev A.Yu., Aleksandrov A.G. The role of proprotein convertase subtilisin/kexin of type 9 (pcsk-9) in cholesterol metabolism and new opportunities of lipid corrective therapy. International Research Journal. 2019; 4–1 (82): 124–6 (in Russ.)]. DOI: 10.23670/IRJ.2019.82.4.025