Advertisement

EGF-A peptides: A promising strategy for PCSK9 inhibition

      PCSK9 inhibitors have recently emerged as a powerful strategy to decrease low-density lipoprotein cholesterol (LDL-C) on top of statin and/or ezetimibe therapy in patients at high cardiovascular (CV) risk [
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • et al.
      2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).
      ]. PCSK9 was discovered in 2003 as the third gene responsible for autosomal dominant hypercholesterolemia (ADH) in two French families, in whom gain-of-function (GOF) variants were identified [
      • Abifadel M.
      • Varret M.
      • Rabes J.P.
      • et al.
      Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
      ]. Shortly after, carriers of PCSK9 loss-of-function (LOF) variants were shown to be characterized by low levels of LDL-C and, as a consequence, by a drastically reduced risk of CV events compared to non-carriers [
      • Cohen J.C.
      • Boerwinkle E.
      • Mosley Jr., T.H.
      • Hobbs H.H.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      ]. Altogether, these genetic findings validated PCSK9 inhibition as a clinically relevant approach to treat hypercholesterolemia and to mitigate CV risk [
      • Cariou B.
      • Le May C.
      • Costet P.
      Clinical aspects of PCSK9.
      ].

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Mach F.
        • Baigent C.
        • Catapano A.L.
        • et al.
        2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).
        Atherosclerosis. 2019 Aug 31; (pii: S0021-9150(19)31459-5)
        • Abifadel M.
        • Varret M.
        • Rabes J.P.
        • et al.
        Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
        Nat. Genet. 2003; 34: 154-156
        • Cohen J.C.
        • Boerwinkle E.
        • Mosley Jr., T.H.
        • Hobbs H.H.
        Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
        N. Engl. J. Med. 2006; 354: 1264-1272
        • Cariou B.
        • Le May C.
        • Costet P.
        Clinical aspects of PCSK9.
        Atherosclerosis. 2011; 216: 258-265
        • Seidah N.G.
        • Awan Z.
        • Chrétien M.
        • Mbikay M.
        PCSK9: a key modulator of cardiovascular health.
        Circ. Res. 2014; 114: 1022-1036
        • Poirier S.
        • Mayer G.
        • poupon V.
        • et al.
        Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route.
        J. Biol. Chem. 2009; 284: 28856-28864
        • Sabatine M.S.
        • Giugliano R.P.
        • Keech A.C.
        • et al.
        Evolocumab and clinical outcomes in patients with cardiovascular disease.
        N. Engl. J. Med. 2017; 376: 1713-1722
        • Schwartz G.G.
        • Steg P.G.
        • Szarek M.
        • et al.
        Alirocumab and cardiovascular outcomes after acute coronary syndrome.
        N. Engl. J. Med. 2018; 379: 2097-2107
        • Lindholm M.W.
        • Elmén J.
        • Fisker N.
        • et al.
        PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates.
        Mol. Ther. 2012; 20: 376-381
        • Ray K.K.
        • Landmesser U.
        • Leiter L.A.
        • et al.
        Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol.
        N. Engl. J. Med. 2017; 376: 1430-1440
        • Valenti V.
        • Noto D.
        • Giammanco A.
        • et al.
        PCSK9-D374Y mediated LDLR degradation can be functionally inhibited by EGF-A and truncated EGF-A peptides: an in vitro study.
        Atherosclerosis. 2020; 292: 209-214
        • Shan L.
        • Pang L.
        • Zhang R.
        • et al.
        PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide.
        Biochem. Biophys. Res. Commun. 2008; 375: 69-73
        • Zhang Y.
        • Eigenbrot C.
        • Zhou L.
        • et al.
        Identification of a small peptide that inhibits PCSK9 binding to the low density lipoprotein receptor.
        J. Biol. Chem. 2014; 289: 942-955
        • 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: 284-294
        • Canuel M.
        • Sun X.
        • Asselin M.C.
        • et al.
        Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1).
        PLoS One. 2013; 8e64145
        • Poirier S.
        • Mayer G.
        • Benjannet S.
        • et al.
        The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2.
        J. Biol. Chem. 2008; 283: 2363-2372
        • Cariou B.
        • Si-Tayeb K.
        • Le May C.
        Role of PCSK9 beyond liver involvement.
        Curr. Opin. Lipidol. 2015; 26 (155–16)
        • Da Dalt L.
        • Ruscica M.
        • Bonacina F.
        • et al.
        PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor.
        Eur. Heart J. 2019; 40: 357-368
        • Tschöp M.H.
        • Finan B.
        • Clemmensen C.
        • et al.
        Unimolecular polypharmacy for treatment of diabetes and obesity.
        Cell Metabol. 2016; 24: 51-62
        • Seidah N.G.
        • Prat A.
        The biology and therapeutic targeting of the proprotein convertases.
        Nat. Rev. Drug Discov. 2012; 11: 367-383

      Linked Article