Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli
Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli
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DOI：
10.1021/jm040818l
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发表时间：
2005-02-24
影响因子：
7.3
通讯作者：
Linusson, A
中科院分区：
文献类型：
--
作者：
Larsson, A;Johansson, SMC;Linusson, A
利用统计分子设计设计了一个针对革兰氏阴性菌菌毛组装至关重要的蛋白质-蛋白质相互作用的肽库。采用高分子肽支架，有7个不同的位置。在建筑块空间中进行选择，并将先前已知的结构-活动数据包含在设计过程中。这导致了一个由32个肽组成的大量减少的文库，由固相合成制备。肽抑制质周伴侣蛋白FimC和菌毛粘附素FimH之间蛋白-蛋白相互作用的能力随后通过ELISA测定。发现了抑制FimC/FimH蛋白（-）蛋白相互作用的新肽，其抑制程度与天然FimC肽相同。ELISA反应的多变量QSAR研究提供了有价值的氨基酸性质信息，这些氨基酸在高分子支架的七个位置上是首选的。该信息可用于开发优化的肽和肽拟物，以抑制病原菌中的菌毛组装。
A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.