A Novel Therapeutic for Invasive Candidiasis

描述(申请人提供)：系统性真菌感染越来越常见，特别是在免疫功能低下的患者中。虽然已经开发了新的抗真菌药物，但与这些感染相关的死亡率仍然很高，特别是由白色念珠菌和其他非白色念珠菌引起的感染(NAS)。这是由于药物的谱系有限，副作用显著，以及耐药性的发展，导致耐药菌株的增加。宿主防御蛋白(HDPs)是一种天然存在的广谱抗菌剂，最近被研究用于治疗抗生素和抗真菌药物。它们的主要优势之一是，微生物通常不会对这些药物产生抗药性。不幸的是，它们的生产成本很高，而且往往对蛋白酶消化敏感。我们已经在体外和体内证明了一系列廉价的非肽低聚物和化合物在结构和活性上模拟HDPs对与口腔念珠菌病相关的临床菌株白念珠菌的有效活性。我们的初步数据显示，在人血清存在的情况下，几种模拟物对临床分离的白色念珠菌具有类似的抗真菌活性，其中一种化合物对播散性念珠菌病小鼠有很强的疗效。我们相信，这些化合物可以为开发抗系统性真菌感染的新疗法奠定基础。我们的目标是确定一种安全有效的HDP模拟物(S)作为治疗播散性念珠菌病的开发先导。

DESCRIPTION (provided by applicant): Systemic fungal infections are increasingly common, especially in immune compromised patients. While new antifungal drugs have been developed, there is still a high mortality associated with these infections, especially those due to Candida albicans, other non-albicans species (NAS). This is due to the limited spectrum of the drugs, significant side effects, as well as the development of resistance, leading to an increase in drug-resistant strains. Host defense proteins (HDPs) 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. We have demonstrated the potent activity of a series of inexpensive non-peptidic oligomers and compounds that mimic HDPs in both structure and activity against clinical strains of C. albicans associated with oral candidiasis, both in vitro and in vivo. Our preliminary data demonstrate similar antifungal activity for several mimetics against clinical isolates of C. albicans in the presence of human serum and one of these compounds was robustly efficacious in a mouse of disseminated candidiasis. We believe these compounds can form the basis for the development of novel therapies against systemic fungal infections. Our goal is to identify a safe and efficacious HDP mimic(s) as a development lead for treatment of disseminated candidiasis.