Retrocyclins: Cyclic mini-defensins that inactivate anthrax toxins

广泛的、长期的目标：发现治疗细菌和病毒的新药(“米尼芬辛”) 基于theta防御素的感染，是一种独特的环状十八肽，对某些革兰氏阳性具有强大的活性 细菌和至少三种主要病毒病原体-H1V-1，HSV-2和流感A。 具体目标：这项建议是基于最近发现的低浓度逆转录周期素和其他 西塔防御素可杀死炭疽杆菌细胞，阻止炭疽杆菌孢子成功萌发，灭活炭疽杆菌 炭疽致死因子(LF)和保护头孢菌素不被炭疽致命毒素杀死，炭疽致命毒素是炭疽致命因子和炭疽致命毒素的混合物 保护性抗原(PA)。我们的具体目标是：1)测试电子防御素和结构上相关的环 研究十八肽在小鼠体内的药代动力学特性和潜在毒性； 2)准确界定其抗菌和抗毒素作用的分子机制；3) 设计、合成和研究新的体外、体内和体内逆转录周期蛋白类似物。 原理：A-防御素(HNPs)是天然存在的多肽抗生素，参与宿主防御 人中性粒细胞的活性。8-防御素是一种较小的多肽抗生素，由白细胞产生。 猴子，但不是人类或黑猩猩。在体外，8-防御素是广谱的病毒进入抑制剂， 对万古霉素耐药肠球菌(VRE)有效，似乎是非常有希望的药物 预防炭疽芽胞引起的感染。 方法：我们将使用体外、活体和计算方法来设计、合成和测试逆周期蛋白样蛋白。 环状十八肽，并确定最有希望的未来发展的候选者。 健康相关和生活语言摘要：关键的生物恐怖主义威胁迫切需要新的毒剂， 比如炭疽病。它们也是迫在眉睫的“自然”威胁，如甲型流感，以及日益增长的 耐抗生素细菌的数量，如VRE。这项建议是专门针对B。 但它的影响也包括许多其他紧急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，因为我们不会用活的炭疽杆菌孢子在小鼠模型中进行体内测试 修订了具体目标。所有剩余的目标都可以在两年的时间内实现。 小灵通

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