Natural Product Protease Inhibitors: Therapeutics for Virulence of Oral Pathogens

天然产物蛋白酶抑制剂：口腔病原体毒力的治疗方法

• 批准号: 7600704
• 负责人: Chifu Brad Huang
• 金额: $ 13.01万
• 依托单位: ORACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600704
• 关键词: Abscess; Acute; Affect; Anaerobic Bacteria; Anti-Infective Agents; Arginine; Bacteria; Bacterial Adhesins; Biological; Biological Factors; Biological Process; Carya; Cells; Characteristics; Chemicals; Chronic; Clinical Trials; Complex; Connective Tissue; Cysteine Protease; Defense Mechanisms; Degradation Pathway; Detection; Disease; Disorder by Site; Dose; Ecology; Effectiveness; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epithelial; Epithelial Cells; Etiology; Exhibits; Forsythia; Frequencies; Gingiva; Gingivitis; Goals; Grant; Growth; Halitosis; Host Defense Mechanism; Human; Immune response; In Situ; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Lesion; Libraries; Life; Link; Literature; Lys-gingipain; Mechanics; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microbe; Microbial Biofilms; Modeling; Mus; Mutation; Nutrient; Oral; Oral cavity; Oral health; Outcome; Pathogenicity; Pathway interactions; Pattern; Pecans; Peptide Hydrolases; Periodontal Diseases; Periodontal Infection; Periodontal Ligament; Periodontitis; Periodontium; Pharmaceutical Resources; Phase; Physiological; Physiology; Phytochemical; Plant Extracts; Plants; Population; Porphyromonas gingivalis; Principal Investigator; Process; Production; Property; Protease Inhibitor; Proteinase-Activated Receptors; Proteins; Receptor Cell; Relative (related person); Reporting; Research; Role; Screening procedure; Signal Transduction; Site; Small Business Technology Transfer Research; Structure; Taxon; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Tooth structure; Treatment Protocols; Treponema denticola; Variant; Virulence; Virulent; alveolar bone; antimicrobial; bactericide; base; chemokine; chymotrypsin; combat; commensal microbes; cytokine; design; enzyme activity; extracellular; gingipain; human disease; improved; in vivo; inhibitor/antagonist; innovation; microbial; microbial colonization; microorganism; mouse model; novel; oral biofilm; oral infection; oral pathogen; pathogen; periodontopathogen; prevent; programs; proteinase T; public health relevance; rapid growth; receptor; research study; response; soft tissue; tooth surface

DESCRIPTION (provided by applicant): Oral infections associated with the gingival margin and subgingival sulcus lead to host inflammatory responses. Gingivitis is primarily a response to the bacteria in plaque. This "disease" affects nearly everyone in the population, at some time during their life. Periodontitis is a multifactorial disease that encompasses the hard and soft tissue, microbial colonization (with/without invasion), inflammatory responses, and adaptive immune responses. Periodontal inflammation and tissue destruction result from variations in the subgingival bacterial ecology that trigger deleterious host responses, with current evidence suggesting altered production and/or release of an array of destructive host mediators that lead to tissue destruction. However, recent studies have supported that certain putative oral pathogens produce a array of physiologic gene products (e.g. proteases) that have the capacity to engage and stimulate various host cell receptors resulting in a substantially enhanced synthesis of biomolecules that have been implicated in tissue destruction (e.g. IL-1ss, TNF1). Thus, while strategies of combating gingivitis are primarily designed to be managed by mechanical and/or nonspecific antimicrobial therapies to decrease the overall magnitude of bacterial challenge in the plaque; targeting periodontitis requires additional considerations relative to unique features of the microbial composition of the biofilms, and potentially critical host cell signaling mechanisms that may be unique to these pathogens. This STTR proposal is focusing on a strategy to identify natural plant-based agents that will inhibit proteases from significant oral pathogens, P. gingivalis, T. denticola, and T. forsythia. These proteases have been shown to relate to disease sites, in vitro growth and survival, production of inflammatory mediators, and in vivo virulence. Thus, interfering with the activity of these crucial molecules should provide an innovative new strategy to biologically interfere with infection and disease processes provoked by these oral pathogens. Gingivitis and periodontitis affect as large a proportion of the global population as any disease(s) known to mankind. Thus, identifying and developing more effective therapeutic regimens targeting aspects of the chronic infection and inflammation would provide a significant benefit to these individuals. Specific Aims are to document the effect of select natural products on the growth, host cell triggering, and virulence capacity of these bacteria. PUBLIC HEALTH RELEVANCE: This STTR proposal aims to evaluate natural products for their ability to improve oral health by developing therapeutic treatments for gingival inflammation and tissue distruction. Specific Aims are to isolate and analyze natural products with anti-proteases properties to treat oral infections/diseases.

描述（由申请人提供）：与龈缘和龈下沟相关的口腔感染导致宿主炎症反应。牙龈炎主要是对菌斑中细菌的反应。这种“疾病”几乎影响到人口中的每一个人，在他们一生中的某个时候。牙周炎是一种多因素疾病，包括软硬组织、微生物定植（有/没有入侵）、炎症反应和适应性免疫反应。牙周炎症和组织破坏是由牙龈下细菌生态的变化引起的，这些变化会引发有害的宿主反应，目前的证据表明，一系列破坏性宿主介质的产生和/或释放发生改变，导致组织破坏。然而，最近的研究支持某些假定的口腔病原体产生一系列生理基因产物（例如蛋白酶），这些产物具有参与和刺激各种宿主细胞受体的能力，从而大大增强了与组织破坏有关的生物分子的合成（例如IL-1ss， TNF1）。因此，虽然对抗牙龈炎的策略主要是通过机械和/或非特异性抗菌治疗来管理，以减少菌斑中细菌攻击的总体程度；针对牙周炎需要额外考虑生物膜微生物组成的独特特征，以及这些病原体可能特有的潜在关键宿主细胞信号传导机制。这项STTR提案的重点是确定一种天然植物基药物的策略，该药物将抑制来自重要口腔病原体牙龈卟啉单胞菌、齿牙卟啉单胞菌和连翘单胞菌的蛋白酶。这些蛋白酶已被证明与疾病部位、体外生长和存活、炎症介质的产生和体内毒力有关。因此，干扰这些关键分子的活性应该提供一种创新的新策略，从生物学上干扰由这些口腔病原体引起的感染和疾病过程。牙龈炎和牙周炎影响全球人口的比例与人类已知的任何疾病一样大。因此，确定和开发针对慢性感染和炎症的更有效的治疗方案将为这些个体提供显着的益处。具体目的是记录选择的自然产物对这些细菌的生长，宿主细胞触发和毒力能力的影响。