Structural requirements for potent versus selective cytotoxicity for antimicrobial dermaseptin S4 derivatives
Structural requirements for potent versus selective cytotoxicity for antimicrobial dermaseptin S4 derivatives
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DOI：
10.1074/jbc.m111071200
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发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Mor, A
中科院分区：
文献类型：
--
作者：
Kustanovich, I;Shalev, DE;Mor, A
为了更好地理解抗菌肽的选择性细胞毒性的结构要求，产生了七种皮抑菌肽S4类似物，并就溶液中的分子组织、与模型磷脂膜的结合特性和细胞毒性特性进行了研究。天然皮抑菌肽S4在溶液中显示出高聚集性和高结合亲和力。这些特性与高细胞毒性相关。然而，当面对质膜被越来越复杂的屏障包围的细胞时，效力逐渐受到限制。增加天然肽的正电荷导致部分解聚，这与更高的结合亲和力和对所有细胞类型的几乎无差别的高细胞毒性相关。发现C-末端疏水结构域负责与膜结合，但不负责其破坏。C末端的截短与N-末端结构域的增加的正电荷相结合，导致短肽具有与母体化合物相似的结合亲和力，但显示出对微生物的选择性活性，对人红细胞的毒性降低。核磁共振衍生的三维结构的三个活性衍生物，使一个共同的两亲性结构的描绘与明确的分离的两个叶的正和负的静电势表面。而空间正静电势大大超出了肽的尺寸，并为效力所需，选择性主要受疏水性影响。本文讨论了这种方法用于设计有效和/或选择性溶细胞肽的有用性。
To better understand the structural requirements for selective cytotoxicity of antimicrobial peptides, seven dermaseptin S4 analogs were produced and investigated with respect to molecular organization in solution, binding properties to model phospholipid membranes, and cytotoxic properties. Native dermaseptin S4 displayed high aggregation in solution and high binding affinity. These properties correlated with high cytotoxicity. Yet, potency was progressively limited when facing cells whose plasma membrane was surrounded by increasingly complex barriers. Increasing the positive charge of the native peptide led to partial depolymerization that correlated with higher binding affinity and with virtually non-discriminative high cytotoxicity against all cell types. The C-terminal hydrophobic domain was found responsible for binding to membranes but not for their disruption. Truncations of the C terminus combined with increased positive charge of the N-terminal domain resulted in short peptides having similar binding affinity as the parent compound but displaying selective activity against microbes with reduced toxicity toward human red blood cells. Nuclear magnetic resonance-derived three-dimensional structures of three active derivatives enabled the delineation of a common amphipathic structure with a clear separation of two lobes of positive and negative electrostatic potential surfaces. Whereas the spatial positive electrostatic potential extended considerably beyond the peptide dimensions and was required for potency, selectivity was affected primarily by hydrophobicity. The usefulness of this approach for the design of potent and/or selective cytolytic peptides is discussed herein.