Novel Antimicrobials: Salivary MUC7 Peptides

新型抗菌剂：唾液 MUC7 肽

• 批准号: 7115328
• 负责人: LIBUSE ANNA BOBEK
• 金额: $ 24.74万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115328
• 关键词: Candida albicans; Saccharomyces cerevisiae; antibacterial agents; antifungal agents; antiinfective agents; biodegradable product; biofilm; candidiasis; clinical research; confocal scanning microscopy; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; gene expression profiling; human subject; laboratory mouse; mass spectrometry; microarray technology; mucins; nonhuman therapy evaluation; nucleic acid biosynthesis; peptide chemical synthesis; pharmacokinetics; polymers; protein biosynthesis; saliva

DESCRIPTION: With the emergence of pathogens resistant to conventional antimicrobials, and toxicity of some antimycotics, there is an urgent need for development of new agents with novel mechanisms of action. One promising source is cationic antimicrobial peptides. We have discovered that human salivary mucin MUC7 peptides (derived from the N-terminus) possess significant and broad-spectrum antimicrobial activity m vitro. These cationic peptides are effective against a variety of fungi (e.g., C. albicans and C. neoformans, organisms responsible for the common opportunistic infections in immunocompromised patients, particularly those with HIV/AIDS), and both Gram-positive and negative bacteria (e.g. S. mutans, implicated in dental caries and P. gingivalis, implicated in periodontal diseases). MUC7 20-mer and 12-mer retain considerable candidacidal activity in physiological-like conditions found in the oral cavity. The 12-mer in combination with histatin-5-12-mer or amphotericin-B acts in a synergistic or additive manner against C. albicans and C. neoformans. A newest addition, 12-mer-D isomer exhibits more potent candidacidal activity in high-ionic strength buffers and in saliva, and is less hemolytic than the 12-mer-L (natural form). These finding support and strengthen our hypothesis that these novel peptides are indeed suitable candidates for therapeutic and preventive antimicrobials. Further, that they will show little or no toxicity toward mammalian cells and will have low tendency to elicit resistance. The work proposed in this application will further evaluate the MUC7 peptide potential as therapeutic agents in vitro and m vivo, and continue to examine their mechanism of action. In Specific Aim 1, MUC7 12-mer peptide antimicrobial activity will be examined in detail, including in combination with other antimicrobial agents. In Specific Aim 2, we will address the mechanism of MUC7 peptide action, including intracellular target(s), potential binding to nucleic acid, inhibition of protein and nucleic acid synthesis, and the effect of MUC7 peptide on C. albicans and S. cerevisiae by gene expression profiling. Specific Aim 3 will address the formulation and in vitro testing of biodegradable polymeric and/or hydrogel polymeric delivery systems for these peptides. In Specific Aim 4, we will test the efficacy of the specifically design delivery systems against fungal infections in vivo models. Altogether, these efforts attempt to move the MUC7 peptides toward the long-range goal of clinical application.

描述：随着病原体对常规抗菌剂的抗性和某些抗菌丝药物的毒性的出现，迫切需要开发具有新型作用机理的新药物。一个有希望的来源是阳离子抗菌肽。我们已经发现，人唾液粘蛋白​​MUC7肽（源自N末端）具有重要的和广泛的抗菌活性M Verto。 These cationic peptides are effective against a variety of fungi (e.g., C. albicans and C. neoformans, organisms responsible for the common opportunistic infections in immunocompromised patients, particularly those with HIV/AIDS), and both Gram-positive and negative bacteria (e.g. S. mutans, implicated in dental caries and P. gingivalis, implicated in periodontal diseases). MUC7 20-MER和12-MER在口腔中发现的类似生理状态的念珠菌活性。 12-MER与Hestatin-5-12-Mer或两性霉素-B结合使用，以协同或添加剂方式对白色念珠菌和新生梭菌起作用。最新的12分-D异构体在高离子强度缓冲液和唾液中表现出更有效的念珠化活性，并且比12-Mer-L（自然形式）的溶血性较小。这些发现支持并加强了我们的假设，即这些新型肽确实是用于治疗和预防性抗菌剂的合适候选者。此外，它们对哺乳动物细胞的毒性很少或没有毒性，并且会引起抗药性的趋势。 本应用中提出的工作将进一步评估MUC7肽潜力作为体外和M Vivo的治疗剂，并继续检查其作用机理。在特定的目标1中，将详细检查MUC7 12-MER肽抗菌活性，包括与其他抗菌剂结合使用。在特定的目标2中，我们将解决MUC7肽作用的机制，包括细胞内靶标，与核酸的潜在结合，蛋白质和核酸合成的抑制以及MUC7肽对基因表达分析的MUC7肽对C. obicans和cerevisiae的影响。具体目标3将解决这些肽的可生物降解聚合物和/或水凝胶聚合物递送系统的制剂和体外测试。在特定目标4中，我们将测试特定设计输送系统针对体内模型中真菌感染的功效。总的来说，这些努力试图将MUC7肽转移到临床应用的远距离目标上。