SALIVARY HISTATIN--THERAPEUTIC AGENT

唾液组氨酸--治疗剂

• 批准号: 6516445
• 负责人: LIBUSE ANNA BOBEK
• 金额: $ 19.53万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516445
• 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，包括患有艾滋病和器官移植受者的患者。 在老年人，牙齿佩戴者和唾液功能障碍的人中，真菌感染也会增加。 许多目前可用的抗真菌剂对越来越多的耐药菌菌株有毒和/或无效。 人唾液组蛋白（HSN）是一组阳离子肽，已证明具有杀真菌活性。 这种特性加上HSN是人体的天然产物，因此很可能无毒会使它们有望具有抗真菌治疗剂。 特别是，组织蛋白杀死白色念珠菌和加密型新形象体的抗氧抗性菌株的能力表明，它们可能具有治疗与艾滋病相关的真菌感染的治疗潜力。在上一个赠款期间，我们使用重组HSN-5变体以及化学合成的HSN-5片段来研究HSN-5（24个氨基酸残基蛋白）的结构功能关系。 在该提案中，我们将探讨HSN可以是有效的天然抗真菌治疗剂的假设，并且如果HSN结构功能关系（特定的AIM 1）及其对C. albicans（特定的AIM 2）（特定的AIM 2），则可以设计具有增强保护功能的HSN变体，可以更好地确定和理解。 基于前两个特定目标的结果和我们先前的结果，我们将设计具有增强活性和/或稳定性的HSN-5变体，并检查它们的潜在适合性，因为它们是体外和体内的抗真菌治疗剂（特定目标3）。 我们还将检查HSN-5和相关变体是否具有针对其他机会性真菌物种的杀真菌活性，并与其他抗真菌剂协同作用（特定目标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HSN，可以用作有效和无毒的天然抗真菌治疗剂，这将有助于超过越来越多的抗药性和机会性真菌列表，从而导致生命威胁生命的疾病。 同一分子也可以用作唾液功能障碍患者的人造唾液成分。总体而言，获得的信息可用于有效设计基于HSN的治疗输送系统，以供将来的临床使用。