Synthesis and characterization of nitroaromatic peptoids: fine tuning peptoid secondary structure through monomer position and functionality.
Synthesis and characterization of nitroaromatic peptoids: fine tuning peptoid secondary structure through monomer position and functionality.
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DOI：
10.1021/jo8023363
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发表时间：
2009-02-20
期刊：
影响因子：
--
通讯作者：
Blackwell HE
中科院分区：
文献类型：
--
作者：
Fowler SA;Luechapanichkul R;Blackwell HE
N-取代甘氨酸低聚物，或类肽，已成为一类重要的折叠体，用于研究生物分子相互作用和作为治疗药物的潜在用途。然而，设计具有预先定义的构象的类肽仍然是一个巨大的挑战。需要新的方法来解决这个问题，对单个单体单位在全球类肽折叠过程中的作用进行系统研究是一种策略。在这里，我们报告了我们通过设计、合成和表征含有硝基芳香单体单元的类肽来实现这一方法的努力。这项工作需要合成一种新的手性胺构建块，(S)-1-(2-硝基苯基)乙胺(S2Ne)，它可以很容易地安装到类肽中使用标准的固相类肽合成技术。我们设计了一系列类肽九聚体，使我们能够探索这种相对缺乏电子和空间位阻的α-手性侧链对类肽结构的影响，即类肽螺纹环和螺旋。类肽的圆二色谱(CD)表明，硝基芳香单体对类肽的二级结构有明显的影响。具体地说，在含有交替的N-(S)-1-苯乙基甘氨酸和Ns2Ne单体的九聚体中，螺环结构被破坏，主要构象为螺旋。事实上，将单个Ns2Ne放置在(Nspe)9的N-末端位置导致了相对于同型单体(Nspe)9的螺纹环结构的不稳定形式。相反，我们观察到N-(S)-1-(4-硝基苯基)乙基甘氨酸(NSNP，一种对硝基单体)在N-末端的掺入稳定了相对于(Nspe)9的螺纹环结构。另外的实验表明，硝基芳香族侧链可以通过调节肽类螺纹环结构中关键的分子内氢键的强度来影响蛋白类螺环结构的折叠。空间相互作用也与Ns2ne单体有关。总体而言，这项研究提供了进一步的证据，证明芳香族侧链结构，即使在单个单体单元中被扰动，也可以强烈地影响局部类肽骨架构象。
N-substituted glycine oligomers, or peptoids, have emerged as an important class of foldamers for the study of biomolecular interactions and for potential use as therapeutic agents. However, the design of peptoids with well-defined conformations a priori remains a formidable challenge. New approaches are required to address this problem, and the systematic study of the role of individual monomer units in the global peptoid folding process represents one strategy. Here, we report our efforts toward this approach through the design, synthesis, and characterization of peptoids containing nitroaromatic monomer units. This work required the synthesis of a new chiral amine building block, (S)-1-(2-nitrophenyl)ethanamine (s2ne), which could be readily installed into peptoids using standard solid-phase peptoid synthesis techniques. We designed a series of peptoid nonamers that allowed us to probe the effects of this relatively electron-deficient and sterically encumbered α-chiral side chain on peptoid structure, namely, the peptoid threaded loop and helix. Circular dichroism (CD) spectroscopy of the peptoids revealed that the nitroaromatic monomer has a significant effect on peptoid secondary structure. Specifically, the threaded loop structure was disrupted in a nonamer containing alternating N-(S)-1-phenylethylglycine (Nspe) and Ns2ne monomers, and the major conformation was helical instead. Indeed, placement of a single Ns2ne at the N-terminal position of (Nspe)9 resulted in a destabilized form of the threaded loop structure relative to the homononamer (Nspe)9. Conversely, we observed that incorporation of N-(S)-1-(4-nitrophenyl)ethylglycine (Nsnp, a para-nitro monomer) at the N-terminal position stabilized the threaded loop structure relative to (Nspe)9. Additional experiments revealed that nitroaromatic side chains can influence peptoid nonamer folding by modulating the strength of key intramolecular hydrogen bonds in the peptoid threaded loop structure. Steric interactions were also implicated for the Ns2ne monomer. Overall, this study provides further evidence that aromatic side chain structure, even if perturbed in a single monomer unit, can strongly influence local peptoid backbone conformation.
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影响因子：
15
作者：
Lee BC;Chu TK;Dill KA;Zuckermann RN
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.95.8.4309
发表时间：
1998-04-14
影响因子：
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