A Novel Antimicrobial Peptide Mimetic For Oral Candidiasis

一种治疗口腔念珠菌病的新型抗菌肽模拟物

• 批准号: 7405070
• 负责人: RICHARD W SCOTT
• 金额: $ 12.56万
• 依托单位: POLYMEDIX, INC,
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405070
• 关键词: Acquired Immunodeficiency Syndrome; Animal Disease Models; Antifungal Agents; Antifungal Antibiotics; Bacteria; Candida; Candida albicans; Candidiasis; Characteristics; Chlorhexidine; Data; Development; Digestion; Divalent Cations; Endogenous Factors; Endopeptidases; Epithelial Cells; Exhibits; Future; Goals; Growth; Health; Human; Immunocompromised Host; In Vitro; Individual; Industrial fungicide; Infection; Kinetics; Lesion; Life; Localized; Mammalian Cell; Measures; Microbe; Numbers; Oral; Oral candidiasis; Oral cavity; Pain; Peptide Hydrolases; Peptides; Phase; Polymers; Relative (related person); Resistance; Resistance development; Risk; Saliva; Salivary; Salts; Series; Serum; Sodium Chloride; Standards of Weights and Measures; Structure; System; Systemic infection; Therapeutic; Therapeutic Agents; antimicrobial drug; antimicrobial peptide; base; cytotoxicity; design; in vitro Assay; in vivo; inhibitor/antagonist; killings; microorganism; mimetics; novel; oral infection; pathogenic bacteria

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.

描述（由申请人提供）：白色念珠菌的口腔感染是人类健康中日益严重的问题。对于免疫功能低下的个体，尤其是患有艾滋病的个体，念珠菌病可导致口腔局部疼痛性病变和危及生命的全身感染。此外，由于使用标准抗真菌治疗，越来越多的感染是由非白色念珠菌 (NAC) 物种引起的。因此，开发能够治疗白色念珠菌感染和 NAC 感染的新疗法至关重要。抗菌肽 (AMP) 是天然存在的广谱抗菌剂，最近对其作为治疗性抗生素和抗真菌剂的用途进行了研究。它们的主要优点是微生物通常不会对这些试剂产生耐药性。不幸的是，它们的生产成本昂贵，并且通常对蛋白酶消化敏感。 Polymedix, Inc. 开发了一系列廉价的非肽低聚物和聚合物，在结构和活性方面均模仿 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类似。本申请的总体假设是这些化合物可以构成开发针对念珠菌感染的新疗法的基础。第一阶段应用的目标是确定具有高活性抗真菌剂最佳标准特征的化合物。为了实现这一目标，建议 1) 确定肽模拟化合物针对念珠菌属物种的最佳体外活性； 2) 确定可能改变化合物体外活性的因素，例如唾液和血清成分； 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肽模拟化合物的鉴定，该化合物表现出对念珠菌物种的最佳杀灭作用，同时对宿主的影响最小。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力的因素，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动物模型中进行进一步研究，以开发其作为治疗剂。口腔念珠菌感染是免疫功能低下个体（例如艾滋病患者）中发现的严重并发症。开发安全有效的药物来治疗这些痛苦的、有时甚至危及生命的感染，同时避免产生念珠菌耐药菌株的风险，这一点至关重要。这里要检查的化合物代表了口服抗真菌剂设计的重要进步。