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 我们的目标是开发一种一流的抑制牙龈假单胞菌定植的口腔生物膜作为治疗牙周炎的方法。 牙周炎。严重的牙周炎影响着超过11%的世界人口，导致数十亿人 美元的直接和间接社会成本，并与一些慢性病有关，包括 自身免疫性、心血管、呼吸系统和神经退行性疾病1、2、4、5、7-9。 牙龈假单胞菌被认为是牙周炎的一种致病菌种，它可以塑造整个牙周炎的微生物。 导致生物失调和组织破坏的群落10-13。临床研究证实，最初的牙龈假单胞菌 定植发生在牙龈下袋14-16之外。牙龈假单胞菌能有效地附着在牙周上。 细菌，如共生性链球菌17-19。这种粘附性调节了P。 牙周炎和驱使定植20-22。因此，抑制牙龈假单胞菌对牙周上细菌的黏附 是减少和预防牙周炎的一个很好的方法。 我们的项目团队最初发现，牙龈假单胞菌对口腔的初始定植是由 牙龈假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，我们在抗原I/II中确定了对这种结合26、27至关重要的一个结构域。一种合成肽 从这个区域衍生出来的，被指定为bar，作为一种有效的牙龈假单胞菌黏附和 生物膜的形成26，27。此外，BAR通过预防牙周炎杆菌的致病作用而抑制其毒力。 严重牙周炎小鼠模型的定植和随后的牙槽骨丢失20。 最近，我们产生了一种针对P的杆状多肽的铅小分子模拟物(称为PG95)。 牙周炎中的牙周炎。PG95抑制牙龈假单胞菌在小鼠体内的生物被膜定植和防止骨丢失 牙周炎模型，但对人体细胞没有毒性。前列环素95的体外应用评价 生物膜模型和小鼠牙周炎模型已经产生了明显的治疗牙周炎的潜力。 基于这些结果，我们的目标是开发一种用于治疗和预防糖尿病的PG95含漱液。 牙周炎。此应用程序旨在开发质量控制分析，定义 可转移到人体临床试验，测定血清和唾液中的稳定性，并证明安全。这个 具体目标是：1)合成PG95，建立一种效价测定方法，并在体外生物被膜中展示其有效性 模型，2)确定最优处方并测定PG95的体外pk，3)确定最大值 小鼠口服PG95的耐受量(MTD)。这些研究的完成将进一步 支持将PG95推向临床开发。