Designed Antibiotic Peptides and Mimetics

设计抗生素肽和模拟物

• 批准号: 7700374
• 负责人: KEVIN H. MAYO
• 金额: $ 499.56万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700374
• 关键词: Amino Acids; Anti-Bacterial Agents; Bacillus anthracis; Bacteria; Biological; Bioterrorism; Chemicals; Class; Communicable Diseases; Development; Dimensions; Drug or chemical Tissue Distribution; Funding; Goals; Life; Membrane; Modification; Molecular; Mus; Peptide Antibiotics; Peptides; Research Project Grants; Side; Surface; Testing; Therapeutic; Toxic effect; Yersinia pestis; bacterial resistance; bactericide; base; biodefense; design; falls; in vitro Assay; in vivo; mimetics; novel; scaffold; small molecule

The overall goal of this research project is to develop small-molecule antibacterial agents (peptides & mimetics) for use against infectious disease related to biodefense. These novel compounds fall into the bacterial membrane-disintegrating class of agents, and as such their use is not likely to promote development of bacterial resistance. The Aims of the research project are: Aim 1. Optimize bactericidal activity of the amphipathic peptide 12mer SC4. The goal is to identify key amino acids in SC4 that promote antibacterial activity, and to maximize activity with the optimal combination of amino acid side-chains and chemical modifications. Aim 2. Design calixarene-based SC4 mimetics. Amphipathic, non-peptidic compounds based on the calixarene scaffold, and molecular dimensions and surface topology of folded peptide SC4, will be designed, synthesized and tested. Information from Aim 1 will be used to guide mimetic design in Aim 2. Aim 3. Assess biological efficacy of bactericidal agents. First, all compounds made under Aims 1 and 2 will be tested in in vitro assays. The most active compounds from Aims 1 and 2 then will be tested in vivo in mice directly challenged with live bacteria. Finally, the one or two best bactericidal agents will be ADMETassessed for clearance, stability, tissue distribution and toxicity in mice. This research project has so far produced novel bactericidal agents that are effective against bioterrorism agents B. anthracis and Y. pestis, among others, and that may be developed as therapeutics.

该研究项目的总体目标是开发小分子抗菌剂（肽和 模拟物）用于针对与生物幻想有关的传染病。这些新颖的化合物落入 细菌膜脱位剂类别的剂，因此它们的使用不太可能促进 细菌抗性的发展。研究项目的目的是： AIM 1。优化两亲性肽12mer SC4的杀菌活性。目标是识别钥匙 SC4中促进抗菌活性的氨基酸，以最佳组合最大化活性 氨基酸的侧链和化学修饰。 AIM 2。设计基于Calixarene的SC4 Mimetics。基于 Calixarene脚手架，折叠肽SC4的分子尺寸和表面拓扑，将设计， 合成和测试。 AIM 1的信息将用于指导AIM 2中的模拟设计。 目标3。评估杀菌剂的生物学功效。首先，所有根据目标1和2制成的化合物将 在体外测定中进行测试。然后，AIMS 1和2的最活跃化合物将在小鼠中在体内进行测试 直接受到活细菌的挑战。最后，将对一个或两个最好的杀菌剂进行治疗 为了清除，稳定性，组织分布和毒性。 迄今为止，该研究项目已经产生了新型的杀菌剂，这些剂有效地抗生物恐怖主义 特工B.炭疽病和Y. Pestis等，可以作为治疗学发展。