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：
8589832
负责人：
DONALD R DEMUTH
金额：
$ 37.28万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589832
关键词：
3-Dimensional A Mouse Accounting Address Adherence Adult Alveolar Bone Loss Animal Model Antigens Atherosclerosis Back Basic Science Biochemical Biological Assay Boxing C-terminal Chemistry Coupled Development Disease Drug Formulations Enzyme-Linked Immunosorbent Assay Event Expenditure 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 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 mimetics 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

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）：牙周炎是一种普遍且昂贵的疾病，主要在口腔中表现出来，但也与诸如动脉粥样硬化和类风湿关节炎等全身性疾病有关。尽管已经将几种生物鉴定为牙周病原体，但最近的一项研究表明，牙龈卟啉单胞菌可能是一种“基石”病原体，它通过诱导炎症的生物膜的人口变化而破坏宿主 - 微生物稳态，从而破坏宿主 - 微生物稳态。因此，防止口腔牙龈牙周牙菌定殖可能不仅限制牙周炎，并对严重的全身性疾病产生积极影响，从而改善了大部分成人人群的健康状况。牙龈疟原虫的理想利基是替代袋，但是在将这种利基生殖于牙龈疟原虫之前，牙龈疟原虫与链球菌中的链球菌相关。这种相互作用是治疗干预的理想目标，因为它代表了促进牙龈疟原虫促进口腔定植的第一个事件之一。构成该提案基础的基础科学发现是由我们先前的工作引起的，表明牙龈疟原虫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械表征导致了肽的发展（指定的棒），该肽会有效抑制口腔的牙龈牙周斑叶片定植。但是，由于肽的生产成本高和降解易感性，因此肽不是理想的治疗剂。该应用程序使用基于结构的方法来设计和合成bar的非肽模拟物。第一个目的将应用我们对酒吧的作用结构和机理的了解，并使用一种创新的合成方法（称为Click Chemistry）设计和化学合成牙龈假单胞菌定植的廉价肽抑制剂。这项研究的第二个目的将评估化合物的生物学活性，以鉴定有效抑制牙龈疟原虫依从性链球菌的铅化合物和牙龈疟原虫生物膜的形成。随后将在AIM 3中测试最活跃的铅化合物，以使用牙周炎动物模型来抑制牙龈斑网毒力。因此，我们先前的机械研究唯一地定位了我们通过专门针对牙龈疟原虫定植的牙周炎及其全身后遗症来设计和开发新的潜在治疗方法。口腔。固有的稳定性和低毒性的化学产品也可能会促进嘴里冲洗，清漆或牙膏中适合临床测试的快速制定。