De novo design of antibacterial β-peptides
De novo design of antibacterial β-peptides
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DOI：
10.1021/ja992728p
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发表时间：
1999-12-29
影响因子：
15
通讯作者：
DeGrado, WF
中科院分区：
文献类型：
--
作者：
Hamuro, Y;Schneider, JP;DeGrado, WF
最近，已经证明许多同分散的、序列特异性的聚合物在溶液中折叠成明确的三维结构。 1-4 在阐明 β-氨基酸短聚合物（β-肽）的构象特性方面取得了特别重大的进展。 2, 3, 5 此类聚酰胺可折叠成圈、螺旋和片状结构，类似于蛋白质的二级结构。 β-肽化学性质稳定，并且能抵抗酶促降解，6 这表明它们可能为仿生聚合物的构建提供一种有吸引力的介质。在这里，我们描述了模仿一类天然膜活性肽毒素和抗生素 7, 8 活性的 β 肽的设计，其中包括马加宁、安博莫丁、天蚕素、蜂毒肽和乳酪素。 9-12 这些肽的生物活性构象已显示由带正电荷的两亲性 R 螺旋组成（图 1）。这些螺旋通过破坏细胞磷脂膜的结构完整性来杀死细胞。 10-19 这些螺旋的整体物理化学性质，而不是它们的精确序列或手性，20, 21 已被认为是活性所需的关键特征。因此，设计基于两亲性β-肽的毒素和抗生素应该是可能的。β-肽形成的一种特别稳定的二级结构是L+2螺旋（也称为14螺旋，或31螺旋；图1），它显示了3个残基的几何重复。 2, 3 β-肽，其中疏水性侧链具有类似的 3-残基
Recently, it has been demonstrated that a number of homodisperse, sequence-specific polymers fold into well-defined threedimensional structures in solution. 1-4 Particularly significant progress has been made in elucidating the conformational properties of short polymers of β-amino acids (β-peptides). 2, 3, 5 This class of polyamides folds into turns, helices, and sheetlike structures, analogous to the secondary structures of proteins. β-Peptides are also chemically stable and resistant to enzymatic degradation, 6 suggesting that they might provide an attractive medium for the construction of biomimetic polymers. Here, we describe the design of β-peptides that mimic the activities of a class of natural membrane-active peptide toxins and antibiotics, 7, 8 which includes magainins, bombolitin, cecropins, melittin, and mastoparans. 9-12 The biological active conformation of these peptides has been shown to consist of a positively charged, amphiphilic R-helix (Figure 1). These helices kill cells by disrupting the structural integrity of their phospholipid membranes. 10-19 The overall physicochemical properties of these helices, and not their precise sequences or chirality, 20, 21 have been proposed to be the key features required for activity. Thus, it should be possible to design amphiphilic β-peptide-based toxins and antibiotics.A particularly stable secondary structure formed by β-peptides is the L+ 2 helix (also known as a 14-helix, or a 31 helix; Figure 1), which shows a 3-residue geometric repeat. 2, 3 β-Peptides in which hydrophobic side chains occur with a similar 3-residue