Novel Context-Activated Protide Anti-Infectives

新型环境激活蛋白肽抗感染药

基本信息

批准号：
7218790
负责人：
Michael R Yeaman
金额：
$ 22.23万
依托单位：
NOVADIGM THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7218790
关键词：
Anti-Infective Agents Antibiotic Resistance Biological Assay Blood Blood Circulation C-terminal Cells Class Consensus Data Defensins Development Disease Drug resistance Endopeptidases Engineering Erythrocytes Evolution Explosion Failure Foundations Genes Genetic Recombination Goals Guanosine Monophosphate Health Host Defense Human In Vitro Incidence Infection Invasive Lead Libraries Life Methods Modeling Molecular Multi-Drug Resistance Mus N-terminal Natural Immunity Nature Organism Outcome Peptide Hydrolases Peptides Phase Phase I Clinical Trials Plasma Prevention Pseudomonas aeruginosa Screening procedure Serum Signal Transduction Small Business Technology Transfer Research Staphylococcus aureus Structure Technology Testing Therapeutic Therapeutic Agents Therapeutic Index Tissues Toxic effect Vascular Endothelial Cell Virulent Whole Blood antimicrobial antimicrobial peptide base chemokine combinatorial cytotoxic cytotoxicity design glutamyl endopeptidase human PPBP protein in vivo innovation methicillin resistant Staphylococcus aureus microbicide novel novel strategies pathogen polypeptide pre-clinical prevent prototype response scaffold

项目摘要

DESCRIPTION (provided by applicant): Antibiotic-resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa are among the most common causes of life-threatening infections in the world. Unfortunately, these infections are increasingly difficult to treat due to the recent explosion in disease caused by methicillin-resistant S. aureus (MRSA) and multi-drug resistant P. aeruginosa (MDRPA). Given their high incidence of causing severe, drug-resistant infections, novel approaches to prevent or treat infections caused by MRSA and MDRPA would have enormous beneficial impact on U.S. and global health. We recently discovered that human platelet microbicidal proteins are microbicidal chemokines, called "kinocidins" to reflect their dual functions. Kinocidins share a consensus structural motif (the ?-core) with classical antimicrobial peptides, and exert rapid and potent microbicidal effects versus pathogens that access the bloodstream, including MRSA and MDRPA. However, kinocidins differ markedly in their overall structural configuration as compared to classical antimicrobial peptides (eg., defensins), the majority of which are cytotoxic or inactivated when released into the bloodstream. Kinocidins are much less cytotoxic to human vascular endothelial cells or erythrocytes in vitro as compared with defensins. In exploring the structural basis for their minimal host toxicity, we made the highly promising discovery that kinocidins disassemble in the context of active infection through cleavage by proteases generated by virulent pathogens, or that emanate from tissues infected by these organisms. Based on this structure-activity paradigm in human kinocidins, we engineered a novel class of polypeptides designed to achieve three critical functions: i) activate in response to signals emanating from virulent organisms or tissues infected thereby; ii) exert potent microbicidal efficacy in relevant contexts, including blood and blood matrices; and iii) have little or no concomitant host cell toxicity as compared with classical antimicrobial peptides. These resulting molecules are termed context-activated protides. We have demonstrated proof of principle by engineering, expressing, and documenting that prototype protides exert 50-fold greater efficacy against MRSA expressing V8 protease than a V8-deficient, avirulent counterpart. Moreover, kinocidin modules retain potent microbicidal activity versus MRSA and MDRPA in whole blood and plasma. Based on these exciting preliminary data, we will assess the feasibility of novel context-activated protides targeting severe MRSA and MDRPA infections. To overcome problems that have contributed to recent failures of antimicrobial peptide therapeutic strategies, and lay the foundations for advancement of context-activated protide technology, our goals for Phase I of the current STTR application are: 1) To generate a combinatorial library of novel context-activated protides using accelerated evolution; 2) To prioritize lead candidate protides for optimal therapeutic index in highly relevant biomatrix assays; and 3) To validate the efficacy of a lead candidate protide in established models of invasive infection. Context-activated protides exploit structural and mechanistic signatures of host defense peptides optimized over millions of years by Nature. This Phase I STTR project is a logical extension of these discoveries, and will validate the feasibility of context-activated protides that target MRSA and MDRPA infections. Outcomes will focus development of lead candidate protides in Phase II of the STTR, to define efficacy against diverse MRSA and MDRPA strains, establish GMP, complete pre-clinical toxicity studies, and submit an IND for phase I clinical trials. This platform technology may also enable otherwise toxic antimicrobial peptides, such as defensins, as therapeutic agents. These advances would represent major breakthroughs in the prevention and treatment of these common and increasingly difficult-to-treat infections.

描述（由申请人提供）：金黄色葡萄球菌和铜绿假单胞菌的抗生素耐药菌菌株是世界上威胁生命的感染的最常见原因之一。不幸的是，由于最近由耐甲氧西林金黄色葡萄球菌（MRSA）和多药耐多药抗铜绿假单胞菌（MDRPA）引起的疾病爆炸，这些感染越来越难以治疗。鉴于它们引起严重，抗药性感染的高发生率，可以预防或治疗由MRSA和MDRPA引起的感染的新方法对美国和全球健康有巨大的有益影响。我们最近发现，人血小板微生物蛋白是微生物趋化因子，称为“激素”，以反映其双重功能。 Kinocidins与经典的抗微生物肽共享共识结构基序（？ - 核），并发挥快速而有效的杀生性效应与获取血液（包括MRSA和MDRPA）的病原体。然而，与经典的抗菌肽（例如，防御素）相比，动力素的整体结构构型明显不同，后者大多数是细胞毒性或释放到血液中时的细胞毒性或灭活。与防御素相比，动力素对人血管内皮细胞的细胞毒性要小得多。在探索其最小宿主毒性的结构基础时，我们提出了一个高度有希望的发现，即动力蛋白在活跃感染的背景下通过由毒物病原体产生的蛋白酶裂解或从这些生物体感染的组织中散发出来。基于这种结构活性范例，我们设计了一种新型的多肽类，旨在实现三个关键功能：i）响应于感染的毒物或组织中发出的信号； ii）在包括血液和血液基质在内的相关情况下发挥有效的杀生性疗效；与经典的抗菌肽相比，III）几乎没有或没有伴随的宿主细胞毒性。这些产生的分子称为上下文激活的蛋白质。我们通过工程，表达和记录了原型蛋白质对MRSA表达V8蛋白酶的疗效比V8缺乏，无效的无毒对应物提出了50倍的疗效。此外，动力学素模块在全血和血浆中保留有效的微生物活性与MRSA和MDRPA。基于这些令人兴奋的初步数据，我们将评估针对严重MRSA和MDRPA感染的新型上下文激活的蛋白质的可行性。为了克服导致抗微生物肽治疗策略的最新失败的问题，并为促进上下文激活的蛋白质技术的发展奠定了基础，我们当前STTR应用的I期目标的目标是：1）生成新颖背景组合库使用加速进化激活的蛋白质； 2）在高度相关的Biomatrix分析中优先考虑铅候选蛋白质的最佳治疗指数； 3）验证铅候选物质在已建立的侵入性感染模型中的疗效。上下文激活的蛋白质利用了数百万年来优化的宿主防御肽的结构和机械特征。该阶段I STTR项目是这些发现的逻辑扩展，并将验证靶向MRSA和MDRPA感染的上下文激活蛋白质的可行性。结局将在STTR的II期中集中铅候选蛋白质的开发，以确定针对多种MRSA和MDRPA菌株的功效，建立GMP，完整的临床前毒性研究，并为I期临床试验提交IND。该平台技术还可以使原本有毒的抗菌肽（例如防御素）作为治疗剂。这些进步将代表预防和治疗这些常见且日益难以治疗的感染的重大突破。