Structure-Based Rational Design of Small α-Helical Peptides with Broad-Spectrum Activity against Multidrug-Resistant Pathogens.
Structure-Based Rational Design of Small α-Helical Peptides with Broad-Spectrum Activity against Multidrug-Resistant Pathogens.
复制标题
抗多药耐药病原菌广谱活性α-螺旋小肽的结构合理设计
DOI：
10.1021/acs.jmedchem.2c01708
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发表时间：
2023-01-12
影响因子：
7.3
通讯作者：
Parang, Keykavous
中科院分区：
文献类型：
--
作者：
Lohan, Sandeep;Konshina, Anastasia G.;Efremov, Roman G.;Maslennikov, Innokentiy;Parang, Keykavous
设计并合成了一系列小的（7 - 12个氨基酸）两亲性阳离子肽，以创造出对细菌细胞具有广谱杀菌活性和选择性的短螺旋肽。分析确定了一种先导的12肽8b，它对革兰氏阳性菌（最低抑菌浓度MIC = 3.1 - 6.2μg/mL）和革兰氏阴性菌（MIC = 6.2 - 12.5μg/mL）具有广谱活性，并且对原核细胞与真核细胞具有选择性（半数溶血浓度HC50 = 280μg/mL，在150μg/mL时细胞存活率>75%）。钙黄绿素染料渗漏试验证明了8b的快速膜溶解作用，并通过扫描电子显微镜得到了证实。根据圆二色性和核磁共振波谱，这些肽在水中具有不规则的空间结构。脂质双层仅在包括8b在内的12肽中诱导出两亲性螺旋。分子动力学模拟提供了关于8b及其最相似物与细菌和哺乳动物膜相互作用的详细信息，并揭示了特定氨基酸在肽的活性和选择性中的作用。
A series of small (7–12 mer) amphipathic cationic peptides were designed and synthesized to create short helical peptides with broad-range bactericidal activity and selectivity toward the bacterial cells. The analysis identified a lead 12-mer peptide 8b with broad-spectrum activity against Gram-positive (MIC = 3.1–6.2 μg/mL) and Gram-negative (MIC = 6.2–12.5 μg/mL) bacteria and selectivity toward prokaryotic versus eukaryotic cells (HC50 = 280 μg/mL, >75% cell viability at 150 μg/mL). The rapid membranolytic action of 8b was demonstrated by a calcein dye leakage assay and confirmed using scanning electron microscopy. According to circular dichroism and NMR spectroscopy, the peptides have an irregular spatial structure in water. A lipid bilayer induced an amphipathic helix only in 12-mer peptides, including 8b. Molecular dynamics simulations provided detailed information about the interaction of 8b and its closest analogues with bacterial and mammalian membranes and revealed the roles of particular amino acids in the activity and selectivity of peptides.
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影响因子：
1.8
作者：
Krylov NA;Efremov RG
通讯作者：
Efremov RG
影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
1.8
作者：
Hassan, Sergio A.;Steinbach, Peter J.
通讯作者：
Steinbach, Peter J.
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
5.5
作者：
Marquette A;Bechinger B
通讯作者：
Bechinger B