Proprotein convertase subtilisin/kexin 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates low-density lipoprotein cholesterol (LDL-c) levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered helical peptides that are able to bind to a cryptic groove site on PCSK9, which is situated in proximity to the main LDLR binding site. Here, we designed potent bipartite PCSK9 inhibitors by appending organic moieties to a helical groove-binding peptide to reach a hydrophobic pocket in the proximal LDLR binding region. The ultimately designed 1-amino-4-phenylcyclohexane-1-carbonyl extension improved the peptide affinity by >100-fold, yielding organo-peptide antagonists that potently inhibited PCSK9 binding to LDLR and preserved cellular LDLR. These new bipartite antagonists have reduced mass and improved potency compared to the first-generation peptide antagonists, further validating the PCSK9 groove as a viable therapeutic target site.

中文翻译：

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二肽PCSK9拮抗剂的有机肽设计。

前蛋白转化酶枯草杆菌蛋白酶/ kexin 9（PCSK9）已成为降脂的重要治疗靶标，因为它通过与肝脏LDL受体（LDLR）结合并影响其细胞内降解来调节低密度脂蛋白胆固醇（LDL-c）的水平。然而，由于缺乏有吸引力的PCSK9靶位，阻碍了小分子抑制剂的发展。我们最近发现了能够结合PCSK9上隐秘凹槽位点的螺旋肽，该位点靠近主要LDLR结合位点。在这里，我们通过将有机部分附加到螺旋凹槽结合肽上以达到近端LDLR结合区域中的疏水性口袋，设计了有效的二分PCSK9抑制剂。最终设计的1-氨基-4-苯基环己烷-1-羰基延伸将肽亲和力提高了100倍以上，产生有效抑制PCSK9与LDLR结合并保留细胞LDLR的有机肽拮抗剂。与第一代肽拮抗剂相比，这些新的二分拮抗剂具有更轻的质量和更高的效能，进一步证实了PCSK9沟是可行的治疗靶位。