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日益严重的问题。在免疫功能低下的个体中，特别是那些患有艾滋病的人，念珠菌病可导致口腔局部但疼痛的病变和危及生命的全身感染。此外，由于使用标准的抗真菌治疗，越来越多的感染是由非白色念珠菌（NAC）引起的。因此，开发既能治疗白色念珠菌感染又能治疗NAC引起的感染的新疗法至关重要。抗菌肽（AMPs）是天然存在的广谱抗菌药物，近年来作为治疗性抗生素和抗真菌药物被研究。它们的主要优点是微生物通常不会对这些药物产生耐药性。不幸的是，它们的生产成本很高，而且往往对蛋白酶消化很敏感。Polymedix公司开发了一系列廉价的非肽低聚物和聚合物，它们在结构和活性上都模仿amp。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致病菌均表现出生长抑制活性。细菌在低浓度的化合物中生长不会产生耐药菌株，这表明它们的作用方式与天然肽相似。这项应用的总体假设是，这些化合物可以为开发针对念珠菌感染的新疗法奠定基础。第一阶段应用的目标是确定具有高活性抗真菌剂的最佳标准的化合物。为此，本文提出：1)确定拟肽化合物对念珠菌的最佳体外活性；2)确定可能改变化合物体外活性的因素，如唾液和血清成分；3)量化肽模拟物对人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肽模拟化合物，该化合物对假丝酵母菌具有最佳的杀灭效果，对宿主的影响最小。此外，我们将确定潜在的活性抑制剂，以及可能提供增强杀伤的因素，以便开发最合适的递送系统。然后，我们将能够使用这种化合物在疾病的动物模型中进行进一步的研究，以开发其作为治疗剂。口腔念珠菌感染是免疫功能低下者（如艾滋病患者）的严重并发症。开发安全有效的药物来治疗这些痛苦的、有时危及生命的感染，而不存在产生耐药念珠菌菌株的风险，这是至关重要的。在这里要检查的化合物代表了一个重要的进展，在设计抗真菌剂的口服应用。

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.