New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
Biopolymers. 2012 May;97(5):253-64. doi: 10.1002/bip.22015. Epub 2011 Dec 14.
Hydrocarbon stapling of peptides is a powerful technique to transform linear peptides into cell-permeable helical structures that can bind to specific biological targets. In this study, we have used high resolution solution NMR techniques complemented by dynamic light scattering to characterize extensively a family of hydrocarbon stapled peptides with known inhibitory activity against HIV-1 capsid assembly to evaluate the various factors that modulate activity. The helical peptides share a common binding motif but differ in charge, the length, and position of the staple. An important outcome of the study was to show the peptides, share a propensity to self-associate into organized polymeric structures mediated predominantly by hydrophobic interactions between the olefinic chain and the aromatic side-chains from the peptide. We have also investigated in detail the structural significance of the length and position of the staple, and of olefinic bond isomerization in stabilizing the helical conformation of the peptides as potential factors driving polymerization. This study presents the numerous challenges of designing biologically active stapled peptides and the conclusions have broad implications for optimizing a promising new class of compounds in drug discovery.
烃类订书肽是一种将线性肽转化为具有细胞渗透性的螺旋结构的强大技术,这种螺旋结构可以与特定的生物靶标结合。在这项研究中,我们使用高分辨率溶液 NMR 技术并辅以动态光散射,对一系列具有已知抑制 HIV-1 衣壳组装活性的烃类订书肽进行了广泛的表征,以评估调节活性的各种因素。这些螺旋肽具有共同的结合基序,但在电荷、订书钉的长度和位置上有所不同。该研究的一个重要结果是表明,这些肽具有将自身缔合形成有组织的聚合结构的倾向,这种聚合结构主要是由烯烃链和肽的芳香侧链之间的疏水相互作用介导的。我们还详细研究了订书钉的长度和位置以及烯烃键异构化在稳定肽的螺旋构象方面的结构意义,这可能是驱动聚合的因素。这项研究提出了设计具有生物活性的订书肽所面临的众多挑战,这些结论对优化药物发现中一类有前途的新化合物具有广泛的意义。