Animal Testing of Biomimetic Antimicrobial Oligomers

描述（由申请人提供）：已经开发了用于设计仿生聚合物的计算方法，该仿生聚合物1）模拟蛋白质的关键生物学特性，2）比天然蛋白质更稳定且生产成本更低。这项技术的第一个应用是设计和合成在健康中起关键作用的宿主防御肽的非肽模拟物，作为对抗各种微生物的第一线攻击。宿主防御肽通常通过破坏细菌膜来发挥其抗微生物作用，而由于膜细胞结构的固有差异，真核细胞不受影响。这些肽是潜在的令人兴奋的治疗剂，因为它们的广谱活性，快速杀菌活性和非常低的细菌耐药性发展的发生率。然而，重大的药物问题，包括全身毒性和制造的困难和费用，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限定长度的低聚物，它们是安全的，具有广泛和有效的抗菌活性，并且合成容易且便宜。重要的是，因为这些化合物模拟宿主防御肽的结构和生物活性，所以细菌耐药菌株的出现是非常不可能发生的。目前，已经合成了八类聚合物和低聚物化合物并测试了其抗微生物活性。从大约150种化合物的小文库中，已经鉴定出几种化合物对一组革兰氏阳性和革兰氏阴性细菌（包括耐药菌株）具有广泛和有效的抗微生物活性。对于几种化合物类别，已经阐明了细菌与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价所研究的低聚物的药学潜力，以鉴定在体内证明抗菌功效而没有明显毒性的化合物或化合物类别。拟定的I期研究涉及通过一系列体外和体内试验将两种对细菌具有选择性细胞毒性的强效寡聚体转移，以评价其在全身性感染动物模型中的疗效。这些I期发现先导化合物研究的结果将用于关注II期的特定化合物类别，以选择开发先导化合物进行彻底的先导化合物优化和开发。

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.