Hicks Rickey P, Bhonsle Jayendra B, Venugopal Divakaramenon, Koser Brandon W, Magill Alan J
Division of Experimental Therapeutics, Walter Reed Army Institute of Research 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA.
J Med Chem. 2007 Jun 28;50(13):3026-36. doi: 10.1021/jm061489v. Epub 2007 Jun 5.
The evolution of drug-resistant bacteria is one of the most critical problems facing modern medicine and requires the development of new drugs that exhibit their antibacterial activity via novel mechanisms of action. One potential source of new drugs could be the naturally occurring peptides that exhibit antimicrobial activity via membrane disruption. To develop antimicrobial peptides exhibiting increased potency and selectivity against Gram positive, Gram negative, and Mycobacterium bacteria coupled with reduced hemolytic activity, peptides containing unnatural amino acids have been designed, synthesized, and evaluated. These compounds were designed on the basis of the electrostatic surface potential maps derived from the NMR determined SDS and DPC micelle-bound conformations of (Ala8,13,18)magainin-2 amide. Unnatural amino acids were incorporated into the polypeptide backbone to control the structural and physicochemical properties of the peptides to introduce organism selectivity and potency. The methods and results of this investigation are described below.
耐药细菌的进化是现代医学面临的最关键问题之一，需要开发通过新作用机制展现抗菌活性的新药。新药的一个潜在来源可能是通过破坏细胞膜展现抗菌活性的天然存在的肽。为了开发对革兰氏阳性菌、革兰氏阴性菌和分枝杆菌具有更高效力和选择性且溶血活性降低的抗菌肽，已设计、合成并评估了含有非天然氨基酸的肽。这些化合物是根据从核磁共振确定的（Ala8,13,18）蛙皮素 - 2酰胺与十二烷基硫酸钠（SDS）和二棕榈酰磷脂酰胆碱（DPC）胶束结合构象得出的静电表面电势图设计的。将非天然氨基酸引入多肽主链以控制肽的结构和物理化学性质，从而引入对生物体的选择性和效力。以下描述本研究的方法和结果。
