Schmitt Margaret A, Weisblum Bernard, Gellman Samuel H
Departments of Chemistry and Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Am Chem Soc. 2007 Jan 17;129(2):417-28. doi: 10.1021/ja0666553.
Host-defense peptides inhibit bacterial growth but manifest relatively little toxicity toward eukaryotic cells. Many host-defense peptides adopt alpha-helical conformations in which cationic side chains and lipophilic side chains are segregated to distinct regions of the molecular surface ("globally amphiphilic helices"). Several efforts have been made to develop unnatural oligomers that mimic the selective antibacterial activity of host-defense peptides; these efforts have focused on the creation of molecules that are globally amphiphilic in the preferred conformation. One such endeavor, from our laboratories, focused on helix-forming alpha/beta-peptides, i.e., oligomers containing a 1:1 pattern of alpha- and beta-amino acid residues in the backbone [Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004, 126, 6848-6849]. We found, unexpectedly, that the most favorable biological activity profile was displayed by a "scrambled" sequence, which was designed not to be able to form a globally amphiphilic helix. Here we report new data, involving an expanded set of alpha/beta-peptides, from experiments designed to elucidate the origins of this surprising result. In addition, we evaluate the susceptibility of alpha/beta-peptides to proteolytic degradation. Our results support the hypothesis that the ability to adopt a globally amphiphilic helical conformation is not a prerequisite for selective antibacterial activity. This conclusion represents a significant advance in our understanding of the relationship among molecular composition, conformation, and biological activity. Our results should therefore influence the design of other unnatural oligomers intended to function as antibacterial agents.
宿主防御肽可抑制细菌生长，但对真核细胞表现出相对较低的毒性。许多宿主防御肽采用α-螺旋构象，其中阳离子侧链和亲脂性侧链被分隔到分子表面的不同区域（“全局两亲性螺旋”）。人们已做出多项努力来开发模仿宿主防御肽选择性抗菌活性的非天然寡聚物；这些努力集中于创造在优选构象中具有全局两亲性的分子。我们实验室的一项此类研究聚焦于形成螺旋的α/β-肽，即主链中α-和β-氨基酸残基呈1:1模式的寡聚物[施密特，M. A.；魏斯布卢姆，B.；盖尔曼，S. H. 《美国化学会志》2004年，126卷，6848 - 6849页]。出乎意料的是，我们发现一种“打乱的”序列展现出最有利的生物活性谱，该序列设计成无法形成全局两亲性螺旋。在此我们报告新的数据，这些数据来自旨在阐明这一惊人结果根源的实验，涉及一组扩充的α/β-肽。此外，我们评估了α/β-肽对蛋白水解降解的敏感性。我们的结果支持这样一种假说，即采用全局两亲性螺旋构象的能力并非选择性抗菌活性的先决条件。这一结论代表了我们在理解分子组成、构象和生物活性之间关系方面的重大进展。因此，我们的结果应会影响旨在用作抗菌剂的其他非天然寡聚物的设计。
