Mowery Brendan P, Lindner Alexandra H, Weisblum Bernard, Stahl Shannon S, Gellman Samuel H
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Am Chem Soc. 2009 Jul 22;131(28):9735-45. doi: 10.1021/ja901613g.
Host-defense peptides are natural antibiotics produced by multicellular organisms to ward off bacterial infection. Since the discovery of these molecules in the 1980s, a great deal of effort has been devoted to elucidating their mechanisms of action and to developing analogues with improved properties for possible therapeutic use. The vast majority of this effort has focused on materials composed of a single type of molecule, most commonly a peptide with a specific sequence of alpha-amino acid residues. We have recently shown that sequence-random nylon-3 copolymers can mimic favorable properties of host-defense peptides, and here we document structure-activity relationships in this polymer family. Although the polymers are heterogeneous in terms of subunit order and stereochemistry, these materials display structure-activity relationships comparable to those that have been documented among host-defense peptides and analogous synthetic peptides. Previously such relationships have been interpreted in terms of a specific and regular folding pattern (usually an alpha-helix), but our findings show that these correlations between covalent structure and biological activity do not require the adoption of a specific or regular conformation. In some cases our observations suggest alternative interpretations of results obtained with discrete peptides.
宿主防御肽是多细胞生物产生的天然抗生素，用于抵御细菌感染。自20世纪80年代发现这些分子以来，人们付出了巨大努力来阐明其作用机制，并开发具有改进特性的类似物以供可能的治疗用途。这项工作的绝大部分都集中在由单一类型分子组成的材料上，最常见的是具有特定α-氨基酸残基序列的肽。我们最近表明，序列随机的尼龙-3共聚物可以模拟宿主防御肽的有利特性，在此我们记录了该聚合物家族中的构效关系。尽管这些聚合物在亚基顺序和立体化学方面是异质的，但这些材料显示出与宿主防御肽和类似合成肽中已记录的构效关系相当。以前，这种关系是根据特定且规则的折叠模式（通常是α-螺旋）来解释的，但我们的研究结果表明，这些共价结构与生物活性之间的相关性并不需要采用特定或规则的构象。在某些情况下，我们的观察结果对使用离散肽获得的结果提出了不同的解释。
