Novel Context-Activated Protide Anti-Infectives

新型环境激活蛋白肽抗感染药

• 批准号: 7429814
• 负责人: Michael R Yeaman
• 金额: $ 22.77万
• 依托单位: NOVADIGM THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429814
• 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

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（由申请方提供）：金黄色葡萄球菌和铜绿假单胞菌的抗生素耐药菌株是世界上危及生命的感染的最常见原因。不幸的是，由于最近由耐甲氧西林沙门氏菌引起的疾病激增，这些感染越来越难以治疗。金黄色葡萄球菌（MRSA）和多重耐药铜绿假单胞菌（MDRPA）。鉴于它们引起严重耐药感染的高发病率，预防或治疗MRSA和MDRPA引起的感染的新方法将对美国和全球健康产生巨大的有益影响。我们最近发现，人血小板杀微生物蛋白是杀微生物趋化因子，称为“kinocidins”，以反映其双重功能。Kinocidins共享一个一致的结构基序（？-核心）与经典的抗菌肽，并发挥快速和有效的杀微生物效果对病原体进入血液，包括MRSA和MDRPA。然而，与经典的抗微生物肽（例如，防御素），其中大部分在释放到血流中时具有细胞毒性或失活。与防御素相比，动杀菌素在体外对人血管内皮细胞或红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，我们做出了非常有希望的发现，即在活性感染的背景下，通过由毒性病原体产生的蛋白酶裂解，或从这些生物体感染的组织中产生的蛋白酶裂解，激肽分解。基于人激肽中的这种结构-活性范例，我们工程化了一类新的多肽，其被设计成实现三个关键功能：i）响应于从毒力生物体或由此感染的组织发出的信号而活化; ii）在相关环境（包括血液和血液基质）中发挥有效的杀微生物功效;以及iii）与经典抗微生物肽相比具有很少或没有伴随的宿主细胞毒性。这些产生的分子被称为上下文激活的磷酰胺酯前体。我们已经通过工程设计、表达和记录证明了原型肽前体对表达V8蛋白酶的MRSA的效力比V8缺陷的无毒对应物高50倍。此外，激肽模块在全血和血浆中保留了对MRSA和MDRPA的有效杀微生物活性。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前药的可行性。为了克服导致最近的抗微生物肽治疗策略失败的问题，并为背景激活的前肽技术的进步奠定基础，我们目前STTR应用的I期的目标是：1）使用加速进化产生新的背景激活的前肽的组合文库; 2）优先考虑在高度相关的生物基质测定中用于最佳治疗指数的先导候选前肽;和3）验证先导候选磷酰胺酯前药在建立的侵袭性感染模型中的功效。上下文激活的磷酰胺酯利用自然界数百万年来优化的宿主防御肽的结构和机制特征。该I期STTR项目是这些发现的逻辑延伸，并将验证靶向MRSA和MDRPA感染的上下文激活的protides的可行性。结果将集中在STTR II期的主要候选药物的开发，以确定对不同MRSA和MDRPA菌株的疗效，建立GMP，完成临床前毒性研究，并提交I期临床试验的IND。该平台技术还可以使原本有毒的抗微生物肽（例如防御素）能够作为治疗剂。这些进展将代表在预防和治疗这些常见和日益难以治疗的感染方面的重大突破。