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

基本信息

批准号：
7463962
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
项目类别：
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/7463962
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 Research Project Grants 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 secondary infection theta-defensin

项目摘要

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

宽阔的长期构造：发现用于治疗细菌和病毒的新药（“ Minidefensins”）感染，基于抑制theta-defensin，独特的环状八度肽，具有有效的活性对某些怪异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. 具体目的：该提案是基于最近发现的，即低浓度的逆转录蛋白和其他抑制theta-defensin可以杀死炭疽芽孢杆菌细胞，防止炭疽芽孢杆菌孢子成功发芽，失活炭疽致死因子（LF），保护头cef不被炭疽致死毒素杀死，LF的混合物和保护性抗原（PA）。我们的具体目的是：1）测试e-防御素和结构相关的循环鼠模型中的体内八度肽，以确定其药代动力学特性和潜在毒性； 2）精确定义负责其抗菌和抗毒性特性的分子机制； 3）设计，合成和研究体内和计算机中的新的另一个类似物。理由：A-二防御素（HNP）是自然存在的肽抗生素，参与宿主防御人类中性粒细胞的活动。 8-防御素是白细胞产生的较小肽抗生素猴子，但不是人类或黑猩猩的猴子。在体外，8-防御素是广谱的病毒进入抑制剂，有效抵抗万古霉素耐药的肠球菌（VRE），并且似乎是高度有希望的药物预防炭疽芽孢杆菌孢子引发的感染。方法：我们将使用体外，IN VIVA和计算方法设计，合成和测试折叠蛋白样循环八度肽，并确定未来发展的最有希望的候选人。健康相关性和外行语言摘要：关键的生物恐怖威胁迫切需要新的代理商，例如炭疽。它们也需要迫在眉睫的“自然”威胁，例如流感，以及成长抗生素耐药菌的数量，例如VRE。该提议专门针对B。炭疽病，但其含义也包括许多其他紧急和未满足的生物医学需求。注意：：原始提案的唯一更改是删除特定目的中的单个单词（有效性） 1，因为我们不会按照小鼠模型中的活体力抗体进行体内测试修订的具体目的。所有其余目标都可以在两年的时间内解决。 PHS