ACS Chem Biol. 2020 Feb 21;15(2):425-436. doi: 10.1021/acschembio.9b00899. Epub 2020 Jan 30.
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.
前蛋白转化酶枯草溶菌素 9（PCSK9）已成为降脂治疗的重要靶点，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）水平。然而，由于缺乏有吸引力的 PCSK9 靶位，小分子抑制剂的开发受到阻碍。我们最近发现了能够与 PCSK9 上一个隐蔽的凹槽部位结合的螺旋肽，该部位位于与主要 LDLR 结合部位相邻的位置。在这里，我们通过将有机部分附加到螺旋凹槽结合肽上来设计有效的双部分 PCSK9 抑制剂，以到达 LDLR 结合区域近端的疏水口袋。最终设计的 1-氨基-4-苯基环己烷-1-羰基扩展部分使肽的亲和力提高了> 100 倍，产生了能够有效抑制 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，这些新的双部分拮抗剂的质量降低，效力提高，进一步验证了 PCSK9 凹槽作为可行的治疗靶位。
