Reid Robert C, Kelso Michael J, Scanlon Martin J, Fairlie David P
Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.
J Am Chem Soc. 2002 May 22;124(20):5673-83. doi: 10.1021/ja0256461.
The beta-strand conformation is unknown for short peptides in aqueous solution, yet it is a fundamental building block in proteins and the crucial recognition motif for proteolytic enzymes that enable formation and turnover of all proteins. To create a generalized scaffold as a peptidomimetic that is pre-organized in a beta-strand, we individually synthesized a series of 15-22-membered macrocyclic analogues of tripeptides and analyzed their structures. Each cycle is highly constrained by two trans amide bonds and a planar aromatic ring with a short nonpeptidic linker between them. A measure of this ring strain is the restricted rotation of the component tyrosinyl aromatic ring (DeltaG(rot) 76.7 kJ mol(-1) (16-membered ring), 46.1 kJ mol(-1) (17-membered ring)) evidenced by variable temperature proton NMR spectra (DMF-d(7), 200-400 K). Unusually large amide coupling constants ((3)J(NH-CHalpha) 9-10 Hz) corresponding to large dihedral angles were detected in both protic and aprotic solvents for these macrocycles, consistent with a high degree of structure in solution. The temperature dependence of all amide NH chemical shifts (Deltadelta/T 7-12 ppb/deg) precluded the presence of transannular hydrogen bonds that define alternative turn structures. Whereas similar sized conventional cyclic peptides usually exist in solution as an equilibrium mixture of multiple conformers, these macrocycles adopt a well-defined beta-strand structure even in water as revealed by 2-D NMR spectral data and by a structure calculation for the smallest (15-membered) and most constrained macrocycle. Macrocycles that are sufficiently constrained to exclusively adopt a beta-strand-mimicking structure in water may be useful pre-organized and generic templates for the design of compounds that interfere with beta-strand recognition in biology.
短肽在水溶液中的β-链构象尚不清楚，但它是蛋白质的基本结构单元，也是蛋白水解酶的关键识别基序，这些酶能够促成所有蛋白质的形成和更新。为了构建一种作为拟肽的通用支架，使其预先形成β-链结构，我们分别合成了一系列由三肽组成的15至22元大环类似物，并分析了它们的结构。每个环都受到两个反式酰胺键和一个平面芳香环的高度限制，它们之间有一个短的非肽连接子。这种环张力的一个度量是组成的酪氨酸芳香环的受限旋转（ΔG(rot) 76.7 kJ mol⁻¹（16元环），46.1 kJ mol⁻¹（17元环）），这通过变温质子核磁共振谱（DMF-d(7)，200 - 400 K）得以证明。在质子性和非质子性溶剂中，这些大环都检测到了异常大的酰胺偶合常数（³J(NH-CHα) 9 - 10 Hz），对应着大的二面角，这与溶液中的高度结构一致。所有酰胺NH化学位移对温度的依赖性（Δδ/T 7 - 12 ppb/℃）排除了定义替代转角结构的跨环氢键的存在。虽然类似大小的传统环肽在溶液中通常以多种构象的平衡混合物形式存在，但这些大环即使在水中也采用明确的β-链结构，二维核磁共振谱数据以及对最小（15元）和最受限大环的结构计算都揭示了这一点。在水中充分受限而专门采用β-链模拟结构的大环，可能是用于设计干扰生物学中β-链识别的化合物的有用的预先组织好的通用模板。
