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.

项目概要 我们的目标是开发一种一流的口腔生物膜牙龈卟啉单胞菌定植抑制剂，作为以下疾病的治疗方法： 牙周炎。严重牙周炎影响着全球 11% 以上的人口，导致数十亿人死亡 给社会带来的直接和间接成本，并与许多慢性病有关，包括 自身免疫性疾病、心血管疾病、呼吸系统疾病和神经退行性疾病1,2,4,5,7-9。 牙龈卟啉单胞菌被认为是牙周炎的致病菌，可以塑造整体微生物群 群落导致生态失调和组织损伤10-13。临床研究证实，初始牙龈卟啉单胞菌 定植发生在龈下袋外14-16。牙龈卟啉单胞菌有效粘附于龈上 细菌，例如共生链球菌17-19。这种粘附调节了 P. 的致病潜力。 gingivalis 并驱动定植20-22。因此，抑制牙龈卟啉单胞菌对龈上细菌的粘附 代表了减少和预防牙周炎的绝佳方法。 我们的项目团队最初发现牙龈卟啉单胞菌在口腔的最初定植是通过 牙龈卟啉单胞菌的次要菌毛抗原（Mfa1）与戈登链球菌17的表面抗原I/II结合， 23-25。随后，我们鉴定了抗原 I/II 中对于这种结合至关重要的结构域 26, 27。 一种合成肽 源自该区域的 BAR，可作为牙龈卟啉单胞菌粘附的有效抑制剂， 生物膜的形成26, 27。此外，BAR 通过阻止牙龈卟啉单胞菌毒力的抑制 严重牙周炎小鼠模型中的定植和随后的牙槽骨丢失20。 最近，我们生成了 BAR 肽的先导小分子模拟物（称为 PG95），以靶向 P. 牙龈炎中的牙龈炎。 PG95 抑制牙龈卟啉单胞菌生物膜定植并防止小鼠骨质流失 牙周炎模型，同时对人体细胞没有毒性。 PG95的体外评估 牙周炎生物膜模型和小鼠模型已显示出治疗牙周炎的明显潜力。 基于这些结果，我们的目标是开发一种 PG95 漱口水，用于治疗和预防 牙周炎。该应用程序旨在开发质量控制测定，定义一种配方 可转移到人体临床试验，确定血清和唾液中的稳定性，并证明安全性。这 具体目标是：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，以及 3) 确定最大 小鼠口服 PG95 后的耐受剂量 (MTD)。这些研究的完成将进一步 支持PG95临床开发的进展。