Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers
Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers
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DOI：
10.1073/pnas.0902663106
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发表时间：
2009-09-01
影响因子：
11.1
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Horne, W. Seth;Johnson, Lisa M.;Gellman, Samuel H.
可以模拟蛋白质表面的非天然寡聚物为阻断生物医学上重要的蛋白质-蛋白质相互作用提供了一种潜在有用的策略。在这里，我们评估了一种基于在 HIV 蛋白 gp41 的多肽序列中组合 α 和 β 氨基酸残基的方法，由于拥有丰富的可用结构和生物学信息，该方法代表了一个极好的测试平台。我们证明 α/β 肽可以模拟关键 gp41 亚基的结构和功能特性。溶液物理研究、晶体学数据以及细胞融合和病毒感染性测定的结果共同表明，gp41 模拟 α/β 肽通过与 gp41 衍生的 α 肽相当的机制有效阻止 HIV 细胞融合。优化的 α/β 肽比类似的 α 肽更不易受到蛋白水解降解的影响。我们的研究结果表明，两阶段设计方法（其中基于序列的 alpha -> beta 替换随后是位点特异性主链刚性化）如何导致自然生物识别过程的物理和生物模拟。
Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important protein-protein interactions. Here we evaluate an approach based on combining alpha- and beta-amino acid residues in the context of a polypeptide sequence from the HIV protein gp41, which represents an excellent testbed because of the wealth of available structural and biological information. We show that alpha/beta-peptides can mimic structural and functional properties of a critical gp41 subunit. Physical studies in solution, crystallographic data, and results from cell-fusion and virus-infectivity assays collectively indicate that the gp41-mimetic alpha/beta-peptides effectively block HIV-cell fusion via a mechanism comparable to that of gp41-derived alpha-peptides. An optimized alpha/beta-peptide is far less susceptible to proteolytic degradation than is an analogous alpha-peptide. Our findings show how a two-stage design approach, in which sequence-based alpha ->beta replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.