SALIVARY HISTATIN--THERAPEUTIC AGENT

真菌感染是一种严重的公共健康威胁，特别是对于日益增长的免疫功能受损患者，包括艾滋病患者和器官移植接受者。在老年人、假牙佩戴者和有唾液功能障碍的人中，真菌感染的发生率也有所上升。许多现有的抗真菌药物对越来越多的耐药真菌菌株是有毒的和/或无效的。人唾液组抑素(HSNS)是一组具有杀菌活性的阳离子多肽。这一特性，再加上HSN是人体的天然产物，因此很可能是无毒的，这使它们成为很有前途的抗真菌治疗药物。特别是，组他汀类药物能够杀死耐唑的白色念珠菌和新生隐球菌，这表明它们可能在治疗与艾滋病相关的真菌感染方面具有治疗潜力。在之前的资助期间，我们使用重组的HSN-5变异体以及化学合成的HSN-5片段来研究HSN-5(24个氨基酸残基蛋白)的结构与功能之间的关系。在这个提案中，我们将探索HSN可以成为有效的天然抗真菌治疗药物的假设，以及如果HSN的结构-功能关系(特异性目标1)及其对白色念珠菌的作用模式(特异性目标2)得到更好的定义和理解，则可以设计出具有增强保护功能的HSN变体。基于前两个特定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，并检查它们在体外和体内作为抗真菌治疗药物的潜在适宜性(特定目标3)。我们还将检查HSN-5和相关变种是否对其他机会性真菌物种具有杀菌活性，并与其他抗真菌药物协同作用(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，这些HSN可以作为有效和无毒的天然抗真菌治疗剂，有助于超过导致危及生命的播散性疾病的耐药和机会性真菌的日益增长的名单。同样的分子也可以用作唾液功能障碍患者的人工唾液成分。总的来说，获得的信息可用于有效地设计基于HSN的治疗给药系统，供未来临床使用。

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.