Retrocyclins: Cyclic mini-defensins that inactivate anthrax toxins

广泛的长期目标：发现用于治疗细菌和病毒的新药（“minidefensins”） 感染，基于θ-防御素，独特的环状十八肽，对某些革兰氏阳性菌具有强效活性 细菌和至少三种主要病毒病原体-H1 V- 1、HSV-2和甲型流感。 具体目标：这项建议是基于最近的发现，低浓度的反环素和其他 θ-防御素可以杀死B。炭疽菌细胞，阻止B.炭疽孢子萌发成功， 炭疽致死因子（LF）和保护头孢菌素不被炭疽致死毒素杀死，LF和 保护性抗原（PA）。我们的具体目标是：1）测试e-防御素和结构相关的环状 在鼠模型中体内研究十八肽，以确定其药代动力学性质和潜在毒性; 2)精确定义负责其抗菌和抗毒性特性的分子机制; 3） 在体外、体内和计算机上设计、合成和研究新的retrocyclin类似物。 基本原理：α-防御素（HNP）是天然存在的肽类抗生素，参与宿主防御 人类中性粒细胞的活动。8-防御素是由白细胞产生的较小的肽类抗生素 但人类和黑猩猩的大脑却没有。在体外，β-防御素是广谱病毒进入抑制剂， 对万古霉素耐药肠球菌（VRE）有效，并且似乎是非常有前途的药物， 防止由B引起的感染。炭疽孢子 方法：我们将采用体外、体内和计算方法设计、合成和测试retrocyclinlike 环十八肽，并确定未来发展的最有前途的候选人。 健康相关性和通俗语言摘要：迫切需要新的制剂来应对主要的生物恐怖主义威胁， 例如炭疽。它们还需要应对迫在眉睫的“自然”威胁，如甲型流感，以及日益增长的 耐药性细菌的数量，如VRE。这个建议是专门针对B的。 炭疽病是一种常见的传染病，但它的影响也包括许多其他迫切和未得到满足的生物医学需求。 注：与原提案相比，唯一的变化是删除了具体目标中的一个字（有效性）。 1，因为我们将不会按照 修订的具体目标。所有剩余的目标都可以在两年的时间内解决。 PHS

Broad, Long Term Obiectives: To discover new drugs ("minidefensins") for treating bacterial and viral infections, based on theta-defensins, unique cyclic octadecapeptides with potent activity against certain Grampositive bacteria and at least three major viral pathogens - H1V- 1, HSV-2, and influenza A. Specific Aims: This proposal is based on the recent discovery that low concentrations of retrocyclins and other theta-defensins can kill B. anthracis cells, prevent B. anthracis spores from germinating successfully, inactivate anthrax lethal factor(LF) and protect cefis from being killed by anthrax lethal toxin, a mixture of LF and protective antigen (PA). Our specific aims are: 1) to test e-defensins and structurally related cyclic octadecapeptides in vivo in murine models to ascertain their pharmacokinetic properties and potential toxicity; 2) to precisely define the molecular mechanisms responsible for their antimicrobial and antitoxic properties; 3) to design, synthesize and study new retrocyclin analogs in vitro, in vivo and in silico. Rationale: a-Defensins (HNPs) are naturally occurring peptide antibiotics that participate in the host defense activities of human neutrophils. 8-defensins are smaller peptide antibiotics that are produced by the leukocytes of monkeys, but not those of humans or chimps. In vitro, 8-defensins are broad-spectrum viral entry inhibitors, are effective against vancomycin-resistant enterococci (VRE), and appear to be highly promising agents to protect against infections initiated by B. anthracis spores. Methods: We will use in vitro, in viva, and computational methods to design, synthesize, and test retrocyclinlike cyclic octadecapeptides and to identify the most promising candidates for future development. Health relatedness and Lay language summary: New agents are urgently needed for key bioterrorism threats, such as anthrax. They are also needed for looming "natural" threats, such as influenza A, and for the growing number of antibiotic-resistant bacteria, such as VRE. This proposal is specifically directed towards B. anthracis, but its implications encompass many other urgent and unmet biomedical needs as well. Note: :The only change from the original proposal is the deletion of a single word (effectiveness) in Specific Aim 1, since we will not be performing in vivo tests with live virulent B.anthracis spores in mouse models as per the revised Specific Aims. All remaining Aims can be addressed in a two-year time period. PHS