Animal Testing of Biomimetic Antimicrobial Oligomers

仿生抗菌低聚物的动物测试

• 批准号: 6735247
• 负责人: RICHARD W SCOTT
• 金额: $ 23.88万
• 依托单位: POLYMEDIX, INC,
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6735247
• 关键词: antiinfective agents; biomimetics; chemical registry /resource; chemical structure function; cytotoxicity; drug adverse effect; drug design /synthesis /production; drug discovery /isolation; laboratory mouse; liver cells; microsomes; pharmacokinetics; polymers; tissue /cell culture

DESCRIPTION (provided by applicant): Computational methodologies have been developed for the design of biomimetic polymers that 1) mimic key biological properties of proteins and 2) are more stable and inexpensive to produce than natural proteins. The first application of this technology has been the design and synthesis of non-peptidic mimics of host defense peptides that play a critical role in health, serving as a first line of attack against a wide range of microbes. The host defense peptides commonly exert their antimicrobial effect by damaging the bacterial membrane, sparing eukaryotic cells because of inherent differences in membrane cytoarchitecture. These peptides are potentially exciting therapeutic agents because of their broad spectrum of activity, rapid bactericidal activity and very low incidence of development of bacterial resistance. However, significant pharmaceutical issues, including systemic toxicity and difficulty and expense of manufacturing, have severely hampered clinical progress. Therefore, we have recently developed nonpeptidic antimicrobial polymers and defined-length oligomers that are safe, have broad and potent antimicrobial activity, and are easy and inexpensive to synthesize. Importantly, because these compounds mimic the structure and biological activity of host defense peptides, the appearance of bacterial resistant strains is very unlikely to occur. Presently, eight classes of polymer and oligomer compounds have been synthesized and tested for antimicrobial activity. From a small library of approximately 150 compounds, several compounds have been identified that have broad and potent antimicrobial activity against a panel of gram positive and gram negative bacteria, including antibiotic-resistant strains. For several of the compound classes, structure/activity relationships for potency and selectivity for bacterial vs. mammalian cell cytotoxicity have been elucidated. The goal of the Phase I studies is to begin the evaluation of the pharmaceutical potential of the oligomers under study to identify compounds or compound classes that demonstrate antimicrobial efficacy in vivo without obvious toxicity. The proposed studies for Phase I involve moving two potent oligomers selectively cytotoxic for bacteria through a series of pilot in vitro and in vivo assays to evaluate efficacy in an animal model of systemic infection. Results from these Phase I discovery lead studies will be used to focus on specific compound classes in Phase II to select development lead compounds for thorough lead optimization and development.

描述（由申请人提供）：已经开发出用于设计仿生聚合物的计算方法，其1）模拟蛋白质的关键生物特性，2）比天然蛋白质更稳定且生产成本更低。该技术的首次应用是设计和合成宿主防御肽的非肽模拟物，其在健康中发挥着关键作用，是对抗多种微生物的第一道防线。宿主防御肽通常通过破坏细菌膜来发挥抗菌作用，由于膜细胞结构的固有差异，真核细胞不会受到影响。这些肽因其广谱活性、快速杀菌活性和极低的细菌耐药性发生率而成为潜在的令人兴奋的治疗剂。然而，重大的制药问题，包括全身毒性以及制造难度和费用，严重阻碍了临床进展。因此，我们最近开发了非肽抗菌聚合物和定长寡聚物，它们是安全的，具有广泛而有效的抗菌活性，并且合成简单且廉价。重要的是，由于这些化合物模仿宿主防御肽的结构和生物活性，因此不太可能出现细菌耐药菌株。目前，已经合成了八类聚合物和低聚物化合物并测试了其抗菌活性。从大约 150 种化合物的小型库中，已鉴定出几种化合物对一组革兰氏阳性和革兰氏阴性细菌（包括抗生素耐药菌株）具有广泛而有效的抗菌活性。对于几种化合物类别，细菌与哺乳动物细胞细胞毒性的效力和选择性的结构/活性关系已被阐明。第一阶段研究的目标是开始评估所研究的低聚物的药物潜力，以确定在体内表现出抗菌功效且没有明显毒性的化合物或化合物类别。拟议的第一阶段研究涉及通过一系列体外和体内试验，转移两种对细菌具有选择性细胞毒性的有效寡聚物，以评估在全身感染动物模型中的功效。这些第一阶段发现先导研究的结果将用于重点关注第二阶段的特定化合物类别，以选择开发先导化合物以进行彻底的先导优化和开发。