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

描述(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，但也与系统性疾病有关，如动脉粥样硬化和类风湿性关节炎。虽然有几种细菌已被鉴定为牙周病原体，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，它通过诱导生物膜中的种群变化来破坏宿主-微生物的动态平衡，从而导致炎症。因此，预防牙龈假单胞菌在口腔中的定植不仅可以限制牙周炎，还可以对严重的系统性疾病产生积极影响，改善相当一部分成年人口的健康状况。牙龈假单胞菌的理想生态位是龈下袋，但在定植这个生态位之前，牙龈假单胞菌与牙龈上生物膜中的链球菌联系在一起。这种相互作用是治疗干预的理想靶点，因为它代表了促进牙龈假单胞菌在口腔中定植的第一批事件之一。形成这一建议基础的基础科学发现来自我们之前的工作，表明牙龈假单胞菌与链球菌的联系是由蛋白质-蛋白质相互作用驱动的。我们对这种相互作用的机械性描述导致了一种多肽(指定为bar)的发展，这种多肽可以有效地抑制牙龈假单胞菌在口腔中的定植。然而，多肽由于其生产成本高和易降解而不是理想的治疗剂。该应用程序使用基于结构的方法来设计和合成BAR的非肽模拟物来解决这些缺点。第一个目标是应用我们对BAR的结构和作用机制的知识，使用一种称为点击化学的创新合成方法来设计和化学合成廉价的牙龈假单胞菌定植的模拟肽抑制剂。这项研究的第二个目的是评估这些化合物的生物活性，以确定能够有效抑制牙龈假单胞菌对链球菌的黏附和牙龈假单胞菌生物被膜形成的先导化合物。最活跃的先导化合物随后将在目标3中使用牙周炎动物模型进行抑制牙龈假单胞菌毒力的测试。因此，我们先前的机械学研究为我们设计和开发新的潜在的牙周炎及其系统性后遗症的治疗方法提供了独特的定位，特别是针对牙周炎和其系统性后遗症的牙龈假单胞菌定植。 口腔。点击化学产品固有的稳定性和低毒性也有助于快速配制适合临床测试的漱口水、清漆或牙膏中的化合物。

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.