Structure-activity studies of 14-helical antimicrobial β-peptides:: Probing the relationship between conformational stability and antimicrobial potency
Structure-activity studies of 14-helical antimicrobial β-peptides:: Probing the relationship between conformational stability and antimicrobial potency
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DOI：
10.1021/ja0270423
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发表时间：
2002-10-30
影响因子：
15
通讯作者：
Gellman, SH
中科院分区：
文献类型：
--
作者：
Raguse, TL;Porter, EA;Gellman, SH
抗菌α-螺旋α-肽是多细胞生物体宿主防御机制的一部分，可以用来治疗对常规抗生素产生抗药性的细菌。Hamuro等人最近的工作。已经表明，能够采用由14个成员的环氢键定义的两亲性螺旋的β-氨基酸低聚物(β-肽)对大肠杆菌具有活性[Hamuro，Y.；Schneider，J.P.；DeGrado，W.F.J.Am化学。SoC。1999年、第121、12200-12201]。我们创建了两个系列的阳离子9-和10-残基两亲性β-肽，以探讨14-螺旋稳定性对抗菌和溶血活性的影响。通过改变刚性反式-2-氨基环己烷羧酸(ACHC)残基和柔性无环残基的比例来调节这些系列中14-螺旋的稳定性。我们以前已经证明，短β-肽中高比例的ACHC残基鼓励水溶液中的14-螺旋结构[Appella，D.H.；Barchi，J.J.；Durell，S.R.；Gellman，S.H.J.Am化学。SoC。1999、121、2309-2310]。本文描述的β-肽的圆二色谱显示在水缓冲溶液中有广泛的14-螺旋种群，但螺旋倾向的这种变化并不会导致对一组四种细菌的抗生素活性的显著变化。其中几个9-MERS显示出与合成Mainin衍生物相当的抗生素活性。在这些9-MERS中，溶血活性随着14-螺旋倾向的增加而略有增加，但所有9-MERS的溶血活性都低于马阿宁衍生物。以前对传统多肽(α-氨基酸残基)的研究在螺旋倾向和抗菌活性之间的关系上提供了相互矛盾的证据。之所以出现这种不确定性，是因为在不改变对抗菌活性重要的参数(例如，净电荷或疏水性)的情况下，线性α-肽中的α-螺旋稳定性只能在有限的范围内变化；使用β-肽可以获得更大范围的螺旋稳定性。例如，线性α-肽在水溶液中表现出显著的α-螺旋形成并表现出抗菌活性是非常罕见的，而这里描述的线性β-肽在水溶液中从完全展开到高度折叠。这项研究表明，β-肽可以成为分析构象稳定性和生物活性之间关系的独特工具。
Antimicrobial a.-helical a-peptides are part of the host-defense mechanism of multicellular organisms and could find therapeutic use against bacteria that are resistant to conventional antibiotics. Recent work from Hamuro et al. has shown that oligomers of beta-amino acids ("beta-peptides") that can adopt an amphiphilic helix defined by 14-membered ring hydrogen bonds ("14-helix") are active against Escherichia coli [Hamuro, Y.; Schneider, J. P.; DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200-12201]. We have created two series of cationic 9- and 10-residue amphiphilic beta-peptides to probe the effect of 14-helix stability on antimicrobial and hemolytic activity. 14-Helix stability within these series is modulated by varying the proportions of rigid trans-2-aminocyclohexanecarboxylic acid (ACHC) residues and flexible acyclic residues. We have previously shown that a high proportion of ACHC residues in short beta-peptides encourages 14-helical structure in aqueous solution [Appella, D. H.; Barchi, J. J.; Durell, S. R.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309-2310]. Circular dichroism of the beta-peptides described here reveals a broad range of 14-helix population in aqueous buffer, but this variation in helical propensity does not lead to significant changes in antibiotic activity against a set of four bacteria. Several of the 9-mers display antibiotic activity comparable to that of a synthetic magainin derivative. Among these 9-mers, hemolytic activity increases slightly with increasing 14-helical propensity, but all of the 9-mers are less hemolytic than the magainin derivative. Previous studies with conventional peptides (a.-amino acid residues) have provided conflicting evidence on the relationship between helical propensity and antimicrobial activity. This uncertainty has arisen because alpha-helix stability can be varied to only a limited extent among linear alpha-peptides without modifying parameters important for antimicrobial activity (e.g., net charge or hydrophobicity); a much greater range of helical stability is accessible with beta-peptides. For example, it is very rare for a linear alpha-peptide to display significant a-helix formation in aqueous solution and manifest antibacterial activity, while the linear beta-peptids described here range from fully unfolded to very highly folded in aqueous solution. This study shows that beta-peptides can be unique tools for analyzing relationships between conformational stability and biological activity.