Peptide structure stabilization by membrane anchoring and its general applicability to the development of potent cell-permeable inhibitors.
Peptide structure stabilization by membrane anchoring and its general applicability to the development of potent cell-permeable inhibitors.
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DOI：
10.1002/cbic.201000563
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发表时间：
2011-04-11
期刊：
影响因子：
3.2
通讯作者：
Tarasova, Nadya I.
中科院分区：
文献类型：
--
作者：
Johannessen, Liv;Remsberg, Jarrett;Gaponenko, Vadim;Adams, Kristie M.;Barchi, Joseph J., Jr.;Tarasov, Sergey G.;Jiang, Sheng;Tarasova, Nadya I.
参与与其结合伙伴相互作用的分离蛋白质基序可用于抑制这些相互作用。然而，与蛋白质片段相对应的多肽往往没有明确的二级或三级结构，因为没有蛋白质分子的其余部分作为支架。这导致相应抑制剂的效力较低。对Hedgehog途径脂肽抑制剂的核磁共振和圆二色谱研究表明，膜锚定使细胞膜发挥支架的作用，促进短肽的折叠。此外，脂肪作用增强了细胞的通透性，增加了膜附近化合物的局部浓度，从而促进了有效的抑制作用。胰岛素样生长因子1受体选择性拮抗剂的产生进一步证实了这种合理方法的普遍适用性，其GI50值在纳摩尔范围内。与蛋白质片段相对应的脂肽被发现是许多非药物分子靶标的有效和选择性抑制物。
Isolated protein motifs that are involved in interactions with their binding partners can be used to inhibit these interactions. However, peptides corresponding to protein fragments tend to have no defined secondary or tertiary structures in the absence of scaffolding by the rest of protein molecule. This results in low potency of corresponding inhibitors. NMR and CD spectroscopy studies of lipopeptide inhibitors of the Hedgehog pathway revealed that membrane anchoring allows the cell membrane to function as a scaffold facilitating folding of short peptides. In addition, lipidation enhances cell permeability and increases the local concentration of the compounds near the membrane thus facilitating potent inhibition. General applicability of this rational approach was further confirmed by generation of selective antagonists of insulin-like growth factor 1 receptor with GI50 values in the nanomolar range. Lipopeptides corresponding to protein fragments were found to serve as potent and selective inhibitors of a number of non-druggable molecular targets.
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