ACYCLIC PROTEGRIN ANALOGUES AS ANTIMICROBIAL AGENTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。前列环素是一种含有半胱氨酸的无环β-折叠多肽，具有极广泛的抗菌活性，可杀死多种微生物。由于即使是最有效的抗生素也出现了耐药性，因此开发新的抗菌肽势在必行。人们正在合成非半胱氨酸前列黄素类似物，以最大限度地减少二硫键的氧化和困难的去保护。PI的长期目标是阐明影响半胱氨酸多肽生物活性的必需氨基酸残基，这是开发非半胱氨酸多肽作为治疗剂的必要前提。具体的假设是，取代的胍残基和季铵基团的引入会增加这些类似物的生物活性。这一假说是基于这样的观察结果：1)取代的胍残基可以促进与复杂受体的结合，2)季铵化合物作为消毒剂、防腐剂和防腐剂。基于这些观察，重点是设计新的抗菌肽。具体目标是：1.合成含全取代胍残基和季铵基团的非半胱氨酸肽类似物。这些类似物将在自动固相合成器上使用标准的Fmoc去保护化学合成。2.阐明了非半胱氨酸肽类似物的二级结构。两亲性结构将使用圆二色谱分析来确定与原始β-折叠结构的任何变化。3.非半胱氨酸肽类似物的生物活性确认。将使用最小抑菌浓度(MIC)方案在各种微生物上测试类似物的生物活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Protegrins are acyclic, cysteine containing beta-sheet peptides that have shown extremely broad-spectrum antimicrobial activity, killing a diverse array of microorganisms. Because resistance is appearing to even the most potent antibiotics, the development of new antimicrobial peptides is imperative. Non-cysteine protegrin analogues are being synthesized to minimize oxidation and difficult deprotection of the disulfide linkage. The PI's long-term goal is to elucidate the necessary amino acid residues affecting the bioactivity of the as necessary prerequisite to the development of non-cysteine peptides as therapeutic agents. The specific hypothesis is that the incorporation of substituted guanidine residues and quaternary ammonium groups would increase the bioactivity of these analogues. This hypothesis is based on the observations that 1) substituted guanidine residues can facilitate binding to complex receptors and 2) quaternary ammonium compounds serve as disinfectants, antiseptics, and preservatives. Based on these observations, the focus is to design new antimicrobial peptides. The specific aims are: 1. Synthesis of non-cysteine peptide analogues incorporated with fully substituted guanidine residues and quaternary ammonium groups. The analogues will be synthesized using standard Fmoc deprotection chemistry on an automated solid phase synthesizer. 2. Elucidation of the secondary structure of the non-cysteine peptide analogues. The amphipathic structures will be elucidated using circular dichroism analysis to determine any change from the original beta-sheet structure. 3. Confirmation of bioactivity of non-cysteine peptide analogues. The bioactivity of the analogues will be tested on various microorganisms using minimum inhibitory concentration (MIC) protocols.