Department of Chemistry and Biotechnology, Graduate School of Engineering , The University of Tokyo , 7-3-1 Hongo , Bunkyo-ku, Tokyo 113-8656 , Japan.
Department of Bioengineering, Graduate School of Engineering , The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 , Japan.
J Am Chem Soc. 2019 Sep 18;141(37):14612-14623. doi: 10.1021/jacs.9b04371. Epub 2019 Aug 23.
The term "peptoids" was introduced decades ago to describe peptide analogues that exhibit better physicochemical and pharmacokinetic properties than peptides. Oligo(-substituted glycine) (oligo-NSG) was previously proposed as a peptoid due to its high proteolytic resistance and membrane permeability. However, oligo-NSG is conformationally flexible, and ensuring a defined shape in water is difficult. This conformational flexibility severely limits the biological application of oligo-NSG. Here, we propose oligo(-substituted alanine) (oligo-NSA) as a peptoid that forms a defined shape in water. The synthetic method established in this study enabled the first isolation and conformational study of optically pure oligo-NSA. Computational simulations, crystallographic studies, and spectroscopic analysis demonstrated the well-defined extended shape of oligo-NSA realized by backbone steric effects. This new class of peptoid achieves the constrained conformation without any assistance of -substituents and serves as a scaffold for displaying functional groups in well-defined three-dimensional space in water, which leads to effective biomolecular recognition.
术语“肽拟似物”几十年前被引入，用于描述比肽具有更好理化性质和药代动力学性质的肽类似物。寡（取代甘氨酸）（oligo-NSG）由于其高抗蛋白水解性和膜透过性，以前被提议为肽拟似物。然而，oligo-NSG 构象灵活，在水中确保确定的形状是困难的。这种构象灵活性严重限制了 oligo-NSG 的生物学应用。在这里，我们提出寡（取代丙氨酸）（oligo-NSA）作为一种在水中形成确定形状的肽拟似物。本研究建立的合成方法实现了对光纯 oligo-NSA 的首次分离和构象研究。计算模拟、晶体学研究和光谱分析表明，通过主链空间位阻效应实现了 oligo-NSA 的明确扩展形状。这种新型肽拟似物在没有任何 -取代基辅助的情况下实现了受限构象，并作为在水中以明确的三维空间展示功能基团的支架，从而实现有效的生物分子识别。
