A Novel Antimicrobial Peptide Mimetic For Oral Candidiasis

描述(由申请人提供)：口腔白色念珠菌感染是人类健康中一个日益严重的问题。对于免疫功能低下的人，特别是那些患有艾滋病的人，念珠菌病可能会导致口腔内局部但痛苦的损害，以及危及生命的系统性感染。此外，由于使用了标准的抗真菌治疗，越来越多的感染是由非白念珠菌(NAC)引起的。因此，开发既能治疗白色念珠菌感染又能治疗由NAC引起的感染的新疗法至关重要。抗菌肽(AMPs)是一种天然存在的广谱抗菌剂，最近因其作为治疗性抗生素和抗真菌药物的用途而受到研究。它们的主要优势之一是，微生物通常不会对这些药物产生抗药性。不幸的是，它们的生产成本很高，而且往往对蛋白酶消化敏感。Polymedix，Inc.开发了一系列廉价的非肽齐聚物和聚合物，在结构和活性上都模拟AMPS。初步数据表明，其中一些化合物在体外对白色念珠菌和口腔病原菌具有生长抑制活性。在低浓度化合物中生长的细菌不会产生抗药性菌株，这表明它们的行为方式与天然多肽相似。这一应用的总体假设是，这些化合物可以形成针对念珠菌感染的新疗法的开发基础。这一第一阶段应用的目标是确定表现出高活性抗真菌药特征的最佳标准集的化合物。为了实现这一目标，建议1)建立多肽模拟物对念珠菌的最佳体外活性；2)确定可能影响化合物体外活性的因素，如唾液和血清成分；3)定量多肽模拟物对人类口腔上皮细胞的细胞毒性。这一阶段的成功完成将导致鉴定出一种对念珠菌具有最佳杀灭效果、对宿主影响最小的多肽模拟物。此外，我们将确定潜在的活性抑制物，以及可能提供增强杀伤力的因素，以开发最合适的递送系统。然后，我们将能够将这种化合物用于进一步的疾病动物模型研究，以开发其作为治疗剂。口腔念珠菌感染是一种严重的并发症，发生在免疫功能低下的人身上，比如那些患有艾滋病的人。开发安全有效的药物来治疗这些痛苦的、有时甚至危及生命的感染，而不会产生念珠菌耐药菌株的风险，是至关重要的。这里要研究的化合物代表了口腔应用抗真菌药物设计的重要进展。

DESCRIPTION (provided by applicant): Oral infections of Candida albicans represent an increasing problem in human health. In immunocompromised individuals, especially those suffering from AIDS, Candidiasis can result in both localized, yet painful lesions in the oral cavity and life-threatening systemic infections. Furthermore, due to the use of standard antifungal treatments, an increasing number of infections are due to non-albicans Candidal (NAC) species. It is thus critical to develop new therapies that can treat both C. albicans infections and those due to NAC. Antimicrobial peptides (AMPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to these agents. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. Polymedix, Inc. has developed a series of inexpensive nonpeptidic oligomers and polymers that mimic AMPs in both structure and activity. Preliminary data indicate that some of these compounds exhibit growth inhibitory activity against both C. albicans and oral pathogenic bacteria in vitro. Growth of bacteria in low concentrations of the compounds does not generate resistant strains of bacteria, suggesting that they act in a similar way to the native peptides. The overall hypothesis of this application is that these compounds can form the basis for the development of novel therapies against Candidal infections. The goal of this first phase application is to identify the compound which exhibits the best set of criteria characteristic of a highly active antifungal agent. Toward that goal it is proposed to 1) Establish the optimal in vitro activities of peptide-mimetic compounds against Candida species; 2) Identify factors, such as salivary and serum components, that might modify in vitro activity of the compounds; and 3) Quantify the cytotoxicity of the peptide mimetics against human oral epithelial cells. Successful completion of this phase will result in the identification of a peptide-mimetic compound that exhibit optimal killing of Candida species, with minimal effect on the host. Furthermore, we will have identified potential inhibitors of the activity, and factors that may provide enhanced killing, in order to develop the most appropriate delivery system. We will then be able to use this compound for further studies in animal models of disease for its development as a therapeutic agent. Oral Candidal infections are serious complications found in immunocompromised individuals, such as those suffering from AIDS. Development of safe and effective agents to treat these painful and sometimes life-threatening infections, without the risk of developing resistant strains of Candida, is essential. The compounds to be examined here represent an important advance in the design of antifungal agents for oral applications.