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

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，但也与全身疾病如动脉粥样硬化和类风湿性关节炎有关。虽然有几种微生物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，它通过诱导生物膜的种群变化来破坏宿主-微生物的稳态，从而导致炎症。因此，预防牙龈卟啉卟啉菌在口腔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，但在此之前，牙龈卟啉单胞菌与龈上生物膜中的链球菌结合。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假单胞菌在口腔定植的第一个事件之一。我们之前的研究表明，牙龈假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，这些基础科学发现构成了这一提议的基础。我们对这种相互作用的机制表征导致了一种肽（指定的BAR）的发展，这种肽可以有效地抑制牙龈假单胞菌在口腔中的定植。然而，由于生产成本高且易降解，多肽并不是理想的治疗剂。这个应用程序解决了这些缺点，使用基于结构的方法来设计和合成非肽模拟的BAR。第一个目标将运用我们对BAR结构和作用机制的了解，设计和化学合成廉价的牙龈假单胞菌定植的拟肽抑制剂，使用一种称为点击化学的创新合成方法。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对链球菌的粘附和牙龈卟啉单胞菌生物膜形成的先导化合物。最活跃的先导化合物随后将在Aim 3中使用牙周炎动物模型测试对牙龈假单胞菌毒力的抑制作用。因此，我们先前的机制研究独特地使我们能够设计和开发新的潜在治疗牙周炎及其系统性后遗症的新方法，专门针对牙龈假单胞菌的定植

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.