Animal Testing of Biomimetic Antimicrobial Oligomers

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，这些聚合物1)模拟蛋白质的关键生物特性，2)比天然蛋白质更稳定，生产成本更低。该技术的第一个应用是设计和合成宿主防御肽的非肽模拟物，宿主防御肽在健康中起着至关重要的作用，作为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，而真核细胞由于其细胞膜结构的固有差异而得以保留。这些多肽具有广谱的活性、快速的杀菌活性和极低的细菌耐药性，是潜在的令人兴奋的治疗剂。然而，重大的药物问题，包括全身毒性和制造的难度和费用，严重阻碍了临床进展。因此，我们最近开发了非肽类抗菌聚合物和定长低聚物，它们安全，具有广泛而有效的抗菌活性，并且易于合成且价格低廉。重要的是，由于这些化合物模拟宿主防御肽的结构和生物活性，细菌耐药菌株的出现是不太可能发生的。目前，已经合成了八类聚合物和低聚物化合物并进行了抗菌活性测试。从大约150种化合物的小文库中，已经确定了几种化合物，它们对一组革兰氏阳性和革兰氏阴性细菌（包括耐药菌株）具有广泛而有效的抗菌活性。对于一些化合物类别，已经阐明了细菌和哺乳动物细胞毒性的效力和选择性的结构/活性关系。I期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而没有明显毒性的化合物或化合物类别。拟议的I期研究包括通过一系列体外和体内试验来评估两种强效低聚物对细菌的选择性细胞毒性，以评估在全身感染动物模型中的疗效。这些I期先导研究的结果将用于II期的特定化合物类别，以选择开发先导化合物进行全面的先导优化和开发。

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.