Retrocyclins: Cyclic mini-defensins that inactivate anthrax toxins

逆转录素：可灭活炭疽毒素的环状迷你防御素

• 批准号: 7897621
• 负责人: Kenneth Alan Bradley
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897621
• 关键词: Address; Anthrax disease; Antibiotic Resistance; Antibiotics; Antigens; Antiviral Agents; Bacillus anthracis; Bacillus anthracis spore; Bacteria; Binding; Bioterrorism; Bontoxilysin; Cells; Cercopithecidae; Chimera organism; Computer Simulation; Computing Methodologies; Cyclins; Cytosol; Data; Defensins; Development; Drug Kinetics; Drug or chemical Tissue Distribution; Effectiveness; Encapsulated; Exotoxins; Future; Generations; Genes; Germany; Germination; Goals; HIV-1; Half-Life; Health; Host Defense; Human; Human Activities; Human Herpesvirus 2; Immune system; In Vitro; Infection; Influenza; Intoxication; Laboratories; Language; Leukocytes; Life; Methods; Modeling; Molecular; Monkeys; Mus; Mutation; New Agents; Nonsense Codon; Pattern Recognition; Peptide Antibiotics; Peptides; Pharmaceutical Preparations; Property; Reproduction spores; Research; Research Activity; Serum; Testing; Time; Toxic effect; Universities; Vancomycin resistant enterococcus; Viral; Virulent; Virus; Virus Diseases; aerosolized; analog; anthrax lethal factor; anthrax toxin; antimicrobial; base; clinically significant; design; in vivo; inhibitor/antagonist; killings; microbial; mouse model; neutrophil; pathogen; pathogenic bacteria; peptide analog; preclinical study; prevent; protective effect; protegrins; retrocyclin; theta-defensin

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

广泛、长期的目标：发现治疗细菌和病毒的新药（“小防御素”） 基于 θ 防御素的感染，独特的环状十八肽，具有针对某些革兰氏阳性菌的有效活性 细菌和至少三种主要病毒病原体 - H1V-1、HSV-2 和甲型流感。 具体目标：该提案基于最近的发现，即低浓度的逆转录环素和其他 θ-防御素可以杀死炭疽杆菌细胞，阻止炭疽杆菌孢子成功萌发，灭活 炭疽致死因子（LF）并保护cefis免受炭疽致死毒素（LF和炭疽致死毒素的混合物）的杀死 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相关的循环 在小鼠模型中进行体内十八肽以确定其药代动力学特性和潜在毒性； 2）精确定义其抗菌和抗毒特性的分子机制； 3） 在体外、体内和计算机上设计、合成和研究新的逆环素类似物。 理由：α-防御素 (HNP) 是天然存在的肽抗生素，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抗生素 猴子的，但不是人类或黑猩猩的。在体外，8-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 防止炭疽芽孢杆菌孢子引发的感染。 方法：我们将使用体外、体内和计算方法来设计、合成和测试类逆环素 环状十八肽并确定未来发展最有希望的候选者。 健康相关性和外行语言摘要：迫切需要新制剂来应对关键的生物恐怖主义威胁， 如炭疽病。它们还需要应对迫在眉睫的“自然”威胁，例如甲型流感，以及日益增长的病毒 抗生素耐药细菌的数量，例如 VRE。该提案专门针对 B. 炭疽病，但其影响还包括许多其他紧迫且未满足的生物医学需求。 注：：与原提案的唯一变化是删除了特定目标中的单个单词（有效性） 1，因为我们不会根据小鼠模型对活毒力炭疽杆菌孢子进行体内测试 修订后的具体目标。所有剩余目标均可在两年内实现。 小灵通