A Novel Small Molecule for the Treatment of Periodontitis

项目摘要 我们的目标是开发一种一流的牙龈卟啉单胞菌口腔生物膜定殖抑制剂，作为治疗 牙周炎严重的牙周炎影响超过11%的世界人口，导致数十亿的 美元的直接和间接成本的社会，并与一些慢性疾病，包括 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。 P.牙龈炎被认为是牙周炎的致病物种，其可以起到塑造整体微生物的作用。 导致生态失调和组织损伤10 -13.临床研究证实，最初的牙龈卟啉单胞菌 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，如链球菌17 -19。这种粘附调节了P. gingivalis和驱动器定植20 -22.因此，抑制牙龈卟啉单胞菌对龈上细菌的粘附 代表了一种减少和预防牙周炎的极好方法。 我们的项目团队最初发现牙龈卟啉单胞菌在口腔中的初始定植是由 牙龈卟啉单胞菌的次要菌毛抗原（Mfa 1）与戈登链球菌17的表面抗原I/II结合， 23-25.随后，我们确定了抗原I/II中对这种结合至关重要的结构域26，27。合成肽 来源于该区域的BAR作为牙龈卟啉单胞菌粘附的有效抑制剂发挥作用， 生物膜的形成26，27.此外，BAR证明了通过预防牙龈卟啉单胞菌毒性而抑制牙龈卟啉单胞菌毒性。 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，我们已经产生了BAR肽的前导小分子模拟物（称为PG 95）以靶向P。 牙周炎中的牙龈炎PG 95抑制牙龈卟啉单胞菌生物膜定殖并防止小鼠骨丢失 牙周炎模型，同时显示对人体细胞没有毒性。PG 95的体外应用评价 生物膜模型和牙周炎的小鼠模型已经产生了作为牙周炎治疗的明显潜力。 基于这些结果，我们的目标是开发一种PG 95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 可转移到人类临床试验，确定在血清和唾液中的稳定性，并证明安全性。的 具体目标是：1）合成PG 95，开发效力测定，并在体外生物膜中证明功效 模型，2）定义最佳制剂并确定PG 95的体外PK，以及3）确定最大 在小鼠中口服施用后PG 95的耐受剂量（MTD）。这些研究的完成将进一步 支持PG 95的临床开发。

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.