Pate Michelle, Blazyk Jack
Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH, USA.
Methods Mol Med. 2008;142:155-73. doi: 10.1007/978-1-59745-246-5_13.
Widespread resistance to antibiotics in current clinical use is increasing at an alarming rate. Novel approaches in antimicrobial therapy will be required in the near future to maintain control of infectious diseases. An enormous array of small cationic peptides exists in nature as part of the innate defense systems of organisms ranging from bacteria to humans. For most naturally occurring linear peptides, such as magainins and cecropins, a common feature is their capacity to form an amphipathic alpha-helix (with polar and nonpolar groups on opposite faces of the helix), a structural feature believed to be important in their antimicrobial function as membrane-lytic agents. A massive effort over the past two decades has resulted in a better understanding of the molecular mechanism of antimicrobial peptides and the production of more potent analogues. To date, however, few of these peptides have been shown to have clinical efficacy, especially for systemic use, in large part due to insufficient selectivity between target and host cells. Recently, we developed a new strategy in the design of antimicrobial peptides. These linear cationic peptides, which form amphipathic beta-sheets rather than alpha-helices, demonstrated superior selectivity in binding to the lipids contained in bacterial vs. mammalian plasma membranes. Here we describe methods to evaluate the structure and function of cationic antimicrobial peptides.
目前临床使用的抗生素普遍耐药性正以惊人的速度增加。在不久的将来，将需要新的抗菌治疗方法来维持对传染病的控制。自然界中存在大量的小阳离子肽，它们是从细菌到人类等生物体固有防御系统的一部分。对于大多数天然存在的线性肽，如蛙皮素和天蚕素，一个共同的特征是它们能够形成两亲性α-螺旋（螺旋的相对面上有极性和非极性基团），这种结构特征被认为在它们作为膜裂解剂的抗菌功能中很重要。在过去二十年中，大量的努力使得人们对抗菌肽的分子机制有了更好的理解，并产生了更有效的类似物。然而，迄今为止，这些肽中很少有被证明具有临床疗效，特别是对于全身使用，很大程度上是由于靶细胞和宿主细胞之间的选择性不足。最近，我们在抗菌肽的设计中开发了一种新策略。这些形成两亲性β-折叠而不是α-螺旋的线性阳离子肽，在与细菌和哺乳动物质膜中所含脂质结合方面表现出卓越的选择性。在这里，我们描述了评估阳离子抗菌肽的结构和功能的方法。
