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Structure-based design and synthesis of peptidominetics targeting P. gingivalis

基于结构的设计和合成针对牙龈卟啉单胞菌的肽动力学

基本信息

批准号：
9271948
负责人：
DONALD R DEMUTH
金额：
$ 37.5万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-23 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9271948
关键词：
Address Adherence Adult Alveolar Bone Loss Animal Model Antigens Atherosclerosis Back Basic Science Biochemical Biological Assay C-terminal Chemicals Chemistry Cost of Illness Coupled Development Disease Enzyme-Linked Immunosorbent Assay Event Expenditure Formulation Foundations Health Health Status Heart Diseases Homeostasis I-antigen Infection Inflammation Knowledge Lead Measures Mediating Microbe Microbial Biofilms Minor Modeling Modification Molecular Models Mouth Diseases Mus Nuclear Receptors Nuclear Structure Oral cavity Organism Outcome Peptide Hydrolases Peptides Periodontitis Population Porphyromonas gingivalis Positioning Attribute Predisposition Prevention Production Protein Binding Domain Proteins Publishing Rheumatoid Arthritis Streptococcus Streptococcus gordonii Structural Models Structural Protein Structure Systemic disease Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Toothpaste Toxic effect United States Variant Varnish Virulence Work base cost cycloaddition design feeding flexibility improved inhibitor/antagonist innovation microbial microbial host molecular modeling mouse model multidisciplinary oral biofilm oral streptococci pathogen peptidomimetics polypeptide prevent protein protein interaction public health relevance research clinical testing scaffold small molecule subgingival biofilm synthetic peptide targeted treatment three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Periodontitis is a widespread and costly disease that is primarily manifest in the oral cavity but is also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. Although several organisms have been identified as periodontal pathogens, a recent study suggests that Porphyromonas gingivalis may be a "keystone" pathogen that disrupts host-microbe homeostasis by inducing populational changes in the biofilm that contribute to inflammation. Thus, preventing P. gingivalis colonization of the oral cavity may not only limit periodontitis and have a positive impact on severe systemic diseases, improving the health status of a significant portion of the adult population. The ideal niche for P. gingivalis is the subgingival pocket, but prior to colonizing this niche, P. gingivali associates with streptococci in the supragingival biofilm. This interaction is an ideal target for therapeutic intervention since it represents one of the first events that promotes colonization of the oral cavity by P. gingivalis. The basic science discoveries that form the foundation for this proposal arise from our previous work showing that the association of P. gingivalis with streptococci is driven by a protein-protein interaction. Our mechanistic characterization of this interaction led to the development of a peptide (designated BAR) that potently inhibits P. gingivalis colonization of the oral cavity. However, peptides are not ideal therapeutic agents due to their high cost of production and susceptibility to degradation. This application addresses these shortcomings using a structure-based approach to design and synthesize non-peptide mimetics of BAR. The first Aim will apply our knowledge of the structure and mechanism of action of BAR to design and chemically synthesize inexpensive peptidomimetic inhibitors of P. gingivalis colonization using an innovative synthetic approach called click chemistry. The second Aim of this study will assess the biologic activity of the compounds to identify lead compounds that potently inhibit P. gingivalis adherence to streptococci and the formation of P. gingivalis biofilms. The most active lead compounds will subsequently be tested in Aim 3 for inhibition of P. gingivalis virulence using an animal model of periodontitis. Thus, our prior mechanistic studies uniquely position us to design and develop new potential treatments for periodontitis and its systemic sequelae by specifically targeting P. gingivalis colonization of the oral cavity. The inherent stability and low toxicity of click chemistry products may also facilitat the rapid formulation of compounds in a mouth rinse, varnish, or toothpaste that will be suitable for clinical testing.

描述（由申请人提供）：牙周炎是一种广泛且昂贵的疾病，主要表现在口腔中，但也与全身性疾病如动脉粥样硬化和类风湿性关节炎相关。虽然几种生物体已被确定为牙周病原体，但最近的一项研究表明，牙龈卟啉单胞菌可能是一种“关键”病原体，其通过诱导生物膜中导致炎症的群体变化来破坏宿主-微生物稳态。因此，预防牙龈卟啉单胞菌在口腔中的定植不仅可以限制牙周炎，还可以对严重的全身性疾病产生积极影响，改善相当一部分成年人的健康状况。牙龈卟啉单胞菌的理想生态位是龈下袋，但在定植于此生态位之前，牙龈卟啉单胞菌与龈上生物膜中的链球菌相关联。这种相互作用是治疗干预的理想靶标，因为它代表了促进牙龈卟啉单胞菌在口腔中定植的最初事件之一。构成这一提议基础的基础科学发现来自我们以前的工作，表明牙龈卟啉单胞菌与链球菌的关联是由蛋白质-蛋白质相互作用驱动的。我们对这种相互作用的机理表征导致开发了一种肽（命名为BAR），其有效抑制牙龈卟啉单胞菌在口腔中的定殖。然而，由于肽的高生产成本和对降解的敏感性，肽不是理想的治疗剂。本申请使用基于结构的方法设计和合成BAR的非肽模拟物来解决这些缺点。第一个目标将应用我们对BAR的结构和作用机制的了解，使用称为点击化学的创新合成方法来设计和化学合成牙龈卟啉单胞菌定植的廉价肽模拟物抑制剂。本研究的第二个目的是评估化合物的生物活性，以确定有效抑制牙龈卟啉单胞菌粘附链球菌和牙龈卟啉单胞菌生物膜形成的先导化合物。随后将在目标3中使用牙周炎动物模型测试最具活性的先导化合物对牙龈卟啉单胞菌毒力的抑制。因此，我们先前的机制研究使我们能够通过特异性靶向牙龈卟啉单胞菌在牙周组织中的定殖来设计和开发用于牙周炎及其全身性后遗症的新的潜在治疗方法。口腔点击化学产品的固有稳定性和低毒性也可以促进化合物在口腔清洗剂、清漆或牙膏中的快速配制，这将适合于临床测试。