A Novel Small Molecule for the Treatment of Periodontitis

一种治疗牙周炎的新型小分子

• 批准号: 10481054
• 负责人: Neil A Fanger
• 金额: $ 30.65万
• 依托单位: VIRTICI, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481054
• 关键词: Adherence; Affect; Aftercare; Alveolar Bone Loss; Antibiotics; Antigens; Autoimmune; Autopsy; Bacteria; Binding; Biochemistry; Biological; Biological Assay; Blood; Cardiovascular system; Cells; Chronic; Clinical Research; Clinical Trials; Consumption; Data; Dental; Dental Calculus; Dental Care; Detection; Development; Direct Costs; Dose; Enzyme-Linked Immunosorbent Assay; Exposure to; Facilities and Administrative Costs; Formulation; Gastrointestinal tract structure; Goals; Health; Hematology; Home; Human; I-antigen; In Vitro; Inflammation; Ingestion; Investments; Lead; Local Anti-Infective Agents; Maximum Tolerated Dose; Mediating; Methods; Microbial Biofilms; Minor; Modeling; Mouth Sore; Mouthwash; Mus; Nerve Degeneration; Nuclear Magnetic Resonance; Oral; Oral Administration; Oral cavity; Oral mucous membrane structure; Organ; Pathogenicity; Peptides; Periodontitis; Persons; Phase; Population; Porphyromonas gingivalis; Positioning Attribute; Prevention; Procedures; Quality Control; Recurrence; Ribosomal RNA; Role; Safety; Saliva; Sampling; Serum; Shapes; Small Business Innovation Research Grant; Societies; Solubility; Stains; Streptococcus; Streptococcus gordonii; Surface Antigens; Time; Tissues; Tooth structure; Toxic effect; Toxicology; United States; Virulence; Work; World Health; aqueous; base; bone loss; clinical development; design; dysbiosis; histopathological examination; improved; inhibitor; irritation; liquid chromatography mass spectrometry; microbial community; microbiome; mimetics; mouse model; novel; oral biofilm; oral microbial community; oral microbiome; pathogenic bacteria; population health; preservation; prevent; procedure cost; reduce symptoms; respiratory; side effect; small molecule; small molecule inhibitor; success; synthetic peptide

Project Summary Our goal is to develop a first-in-class inhibitor of P. gingivalis colonization of oral biofilms as a treatment for periodontitis. Severe periodontitis affects more than 11% of the world's population, resulting in billions of dollars of direct and indirect costs to society, and is associated with a number of chronic conditions including autoimmune, cardiovascular, respiratory, and neurodegenerative diseases1, 2, 4, 5, 7-9. P. gingivalis is considered a causative species in periodontitis that can function to shape the overall microbial community leading to dysbiosis and tissue damage10-13. Clinical research has confirmed that initial P. gingivalis colonization occurs outside the subgingival pocket14-16. P. gingivalis adheres efficiently to supragingival bacteria such as commensal streptococci17-19. This adherence modulates the pathogenic potential of P. gingivalis and drives colonization20-22. Thus, inhibiting the adherence of P. gingivalis to supragingival bacteria represents an excellent approach to reducing and preventing periodontitis. Our project team originally discovered that initial colonization of the oral cavity by P. gingivalis is mediated by the minor fimbrial antigen (Mfa1) of P. gingivalis binding to the surface antigen I/II of Streptococcus gordonii17, 23-25. Subsequently, we identified a domain in antigen I/II essential to this binding26, 27. A synthetic peptide derived from this region, designated BAR, functions as a potent inhibitor of P. gingivalis adherence and formation of biofilms26, 27. In addition, BAR demonstrates inhibition of P. gingivalis virulence by preventing colonization and subsequent alveolar bone loss in mouse models of severe periodontitis20. More recently, we have generated a lead small molecule mimetic of the BAR peptide (called PG95) to target P. gingivalis in periodontitis. PG95 inhibits P. gingivalis colonization of biofilms and prevents bone loss in mouse models of periodontitis, while showing no toxicity to human cells. The assessment of PG95 using in vitro biofilm models and the mouse model of periodontitis has yielded clear potential as a treatment of periodontitis. Based on these results, our goal is to develop a PG95 mouth rinse for the treatment and prevention of periodontitis. This application is designed to develop quality control assays, define a formulation that is transferable to human clinical trials, determine stability in serum and saliva, and demonstrate safety. The specific aims are to: 1) synthesize PG95, develop a potency assay, and demonstrate efficacy in in vitro biofilm models, 2) define an optimal formulation and determine in vitro PK for PG95, and 3) determine the maximum tolerated dose (MTD) of PG95 following oral administration in mice. Completion of these studies will further support the advancement of PG95 towards clinical development.

项目摘要 我们的目标是开发口服生物膜的牙龈假单胞菌定植的第一类抑制剂作为治疗方法 牙周炎。严重的牙周炎影响了世界人口的11％以上，导致数十亿 向社会的直接和间接成本的美元成本，与许多慢性条件有关 自身免疫性，心血管，呼吸道和神经退行性疾病1、2、4、5、7-9。 牙龈疟原虫被认为是牙周炎中的病因，可以发挥作用以塑造整体微生物 社区导致营养不良和组织损伤10-13。临床研究证实了初始牙龈疟原虫 殖民化发生在supgingival Pocket14-16之外。牙龈疟原虫有效地粘附在上下 细菌，例如共生链球菌17-19。这种依从性调节了P的致病潜力。 牙龈和驱动定植20-22。因此，抑制牙龈疟原虫对上菌细菌的依从性 代表了减少和预防牙周炎的出色方法。 我们的项目团队最初发现，牙龈疟原虫对口腔的最初殖民化是由 牙龈疟原假单胞菌与链球菌的表面抗原I/II的少量纤维抗原（MFA1）， 23-25。随后，我们确定了抗原I/II中的一个结构域，对这种结合26，27。一种合成肽 源自该区域的指定条，是牙龈疟原虫依从性的有效抑制剂和 生物膜的形成26，27。此外，bar通过防止抑制了牙龈疟原虫的毒力。 在严重牙周炎的小鼠模型中，定植和随后的肺泡骨质流失20。 最近，我们产生了一个铅的小分子模拟于靶标。 牙周炎中的牙龈。 PG95抑制生物膜的牙龈疟原虫定植，并防止小鼠骨质流失 牙周炎模型，同时对人类细胞没有毒性。使用体外评估PG95 生物膜模型和牙周炎的小鼠模型已作为牙周炎的治疗产生了明显的潜力。 基于这些结果，我们的目标是开发PG95口冲洗以治疗和预防 牙周炎。该应用程序旨在开发质量控制测定法，定义一个公式 可转移到人类临床试验中，确定血清和唾液的稳定性，并证明安全性。这 具体目的是：1）合成PG95，开发效力测定并在体外生物膜中证明功效 模型，2）定义最佳配方并确定PG95的体外PK，3）确定最大 在小鼠口服后，PG95的耐受剂量（MTD）。这些研究的完成将进一步 支持PG95促进临床发展。