Development and functional analysis of novel PCSK9/LDLR interaction inhibitors for hypercholesterolemia treatment

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  • Yokoyama Takumi
    Dept. Life Environ. Sci., Integr. Grad. Sch. Med. Eng. Agr. Sci., Yamanashi Univ.
  • Ando Takehiro
    Dept. Life Environ. Sci., Integr. Grad. Sch. Med. Eng. Agr. Sci., Yamanashi Univ.
  • Fuji Daisuke
    Dept. Biotechnol., Fac. Life Environ. Sci., Yamanashi Univ.
  • Yamamoto Mizuki
    Dept. Integr. Appl. Life Sci., Integr. Grad. Sch. Med. Eng. Agr. Sci., Yamanashi Univ.
  • Kawakami Takashi
    Fac. Life Environ. Sci., Grad. Fac. Interdiscip. Res., Yamanashi Univ. JST, PRESTO

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Other Title
  • 高LDLコレステロール血症治療のための新規PCSK9/LDLR間相互作用阻害剤の開発と機能解析

Abstract

<p>Hypercholesterolemia characterized by excessively elevated levels of plasma low-density lipoprotein-cholesterol (LDLc) increases the risk of atherosclerosis, causing cardiovascular disease and cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), which is secreted from liver, interacts with LDL-receptor (LDLR) that uptakes LDLc from plasma into hepatocytes. The PCSK9-LDLR interaction leads degradation of the LDLR on hepatocytes, resulting in elevation of plasma LDLc levels. Although anti-PCSK9 antibodies that inhibit PCSK9-LDLR interaction have been used for the treatment of hypercholesterolemia, the antibody agents are very expensive because they are produced using mammalian cells. To overcome this problem, it is necessary to develop PCSK9/LDLR interaction inhibitors that are produced by chemical synthesis to be low-cost in hypercholesterolemia  treatment.</p><p>　Here, we report the discovery of novel cyclic peptides that bind to PCSK9 by using the mRNA display evolution based on an Escherichia coli reconstituted cell-free translation system (PURE system) combined with genetic code expansion technique and functional analysis of the cyclic peptides.</p>

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