SALIVARY HISTATIN--THERAPEUTIC AGENT

唾液组氨酸--治疗剂

• 批准号: 6175959
• 负责人: LIBUSE ANNA BOBEK
• 金额: $ 18.92万
• 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 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175959
• 关键词: AIDS therapy; Aspergillus; Candida albicans; Cryptococcus neoformans; antifungal agents; binding proteins; candidiasis; chimeric proteins; confocal scanning microscopy; disease /disorder model; drug delivery systems; drug design /synthesis /production; drug interactions; fluorescence microscopy; genetic strain; human tissue; immunoelectron microscopy; laboratory rat; light microscopy; molecular dynamics; opportunistic infections; protein structure function; proteolysis; saliva; secretory protein

Fungal infections are a serious public-health hazard, particularly for the growing population of immunocompromised patients, including those with AIDS and organ transplant recipients. A rise in fungal infections is also seen in elderly people, denture wearers and individuals with salivary dysfunction. Many presently available antifungal agents are toxic and/or not effective against an increasing number of the drug-resistant fungal strains. Human salivary histatins (Hsns) are a group of cationic peptides that have been shown to possess fungicidal activity. This property coupled with the fact that Hsns are natural products of the human body and thus most likely nontoxic makes them promising antifungal therapeutic agents. In particular, the ability of histatins to kill azole-resistant strains of C. albicans and Cryptococcus neoformans indicates that they may have therapeutic potential in treating fungal infections associated with AIDS. During the previous grant period, we examined the structure- function relationship of Hsn-5 (24 amino acid residue protein) with respect to its candidacidal activity using recombinant Hsn-5 variants as well as chemically synthesized Hsn-5 fragments. In this proposal, we will explore the hypotheses that Hsns can be effective natural antifungal therapeutic agents and that Hsn variants with enhanced protective functions can be designed if the Hsn structure-function relationship (Specific Aim 1) and its mode of action on C. albicans (Specific Aim 2) are better defined and understood. Based on the outcomes from the first two specific aims and our previous results, we will design Hsn-5 variants with enhanced activity and/or stability and examine them for their potential suitability as antifungal therapeutic agents both in vitro and in vivo (Specific Aim 3). We will also examine whether Hsn-5 and relevant variants possess fungicidal activity against other opportunistic fungal species, and act synergistically with other antifungal agents (Specific Aim 4). The long-term objective of this research is to design and produce novel Hsns with enhanced protective function that may serve as effective and non-toxic natural antifungal therapeutic agents that would help to outpace the growing list of the drug resistant and opportunistic fungi causing life-threatening, disseminated diseases. The same molecules could also be used as components of artificial saliva for patients with salivary dysfunction. Collectively, the information obtained can be used to effectively design Hsn-based therapeutic delivery systems for future clinical use.

真菌感染是一种严重的公共卫生危害，特别是对于不断增长的免疫功能低下患者群体，包括艾滋病患者和器官移植接受者。 老年人、假牙佩戴者和唾液功能障碍患者的真菌感染率也有所上升。 许多目前可用的抗真菌剂是有毒的和/或对越来越多的耐药真菌菌株无效。 人唾液组蛋白 (Hsns) 是一组已被证明具有杀菌活性的阳离子肽。 这一特性加上 Hsns 是人体的天然产物，因此很可能无毒，使它们成为有前途的抗真菌治疗剂。 特别是，组氨酸能够杀死白色念珠菌和新生隐球菌的唑类抗性菌株，这表明它们可能具有治疗与艾滋病相关的真菌感染的潜力。在之前的资助期间，我们使用重组 Hsn-5 变体以及化学合成的 Hsn-5 片段检查了 Hsn-5（24 个氨基酸残基蛋白）与其念珠菌活性的结构功能关系。 在本提案中，我们将探讨以下假设：Hsn 可以成为有效的天然抗真菌治疗剂，如果更好地定义和理解 Hsn 结构-功能关系（具体目标 1）及其对白色念珠菌的作用方式（具体目标 2），则可以设计具有增强保护功能的 Hsn 变体。 根据前两个具体目标的结果和我们之前的结果，我们将设计具有增强活性和/或稳定性的 Hsn-5 变体，并在体外和体内检查它们作为抗真菌治疗剂的潜在适用性（具体目标 3）。 我们还将研究Hsn-5和相关变体是否对其他机会性真菌具有杀菌活性，并与其他抗真菌药物协同作用（具体目标4）。这项研究的长期目标是设计和生产具有增强保护功能的新型 Hsns，这些 Hsns 可以作为有效且无毒的天然抗真菌治疗剂，有助于战胜日益增长的导致危及生命的传播性疾病的耐药性和机会性真菌。 同样的分子也可以用作唾液功能障碍患者的人工唾液的成分。总的来说，获得的信息可用于有效设计基于 Hsn 的治疗递送系统，以供未来临床使用。