A Novel Peptide for the Oral Treatment and Prevention of P. Gingivalis Infection

Project Summary Our goal is to develop a first-in-class oral peptide inhibitor for the treatment and prevention of gingivitis and periodontitis. Oral infection by P. gingivalis leads to inflammation and bleeding of the gums, called gingivitis, and eventually bone and tooth loss, called periodontitis3. Almost 50% of adults worldwide over the age of thirty have periodontal disease, making it one of the most common infections in humans11, 72. P. gingivalis infection is also closely associated with several other chronic health conditions, including Alzheimer’s disease, cardiovascular disease, cancer, and arthritis9, 12-16, 27. P. gingivalis is considered a causative species in periodontitis that can function to shape the overall microbial community leading to dysbiosis and tissue damage4-7. Clinical research has confirmed that initial P. gingivalis colonization occurs outside the subgingival pocket38-40. P. gingivalis adheres efficiently to supragingival bacteria such as commensal streptococci32-34. This adherence modulates the pathogenic potential of P. gingivalis and drives colonization35-37. 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 SspB of Streptococcus gordonii32, 42-44. Subsequently, we identified a domain in SspB essential to this binding45, 46. A synthetic peptide derived from this region functions as a potent inhibitor of P. gingivalis adherence and formation of biofilms45, 46. In addition, the synthetic peptide demonstrates inhibition of P. gingivalis virulence by preventing colonization and subsequent alveolar bone loss in mouse models of severe periodontitis35. Building from this innovative work, our objective is to advance this first-in-class, cyclic peptide (called VTC-880) towards the clinic for the treatment and prevention of gingivitis and periodontitis. The key aims of this proposal are to: 1) manufacture VTC-880 and establish potency and analytical assays, 2) determine the optimal formulation and in vitro PK of VTC-880 in human saliva, 3) establish the oral PK and optimal effective dose for VTC-880 in mice, 4) generate acute toxicology profiles for VTC-880 in mice and in a human saliva biofilm model, and 5) finalize our IND-enabling and clinical study plan to advance VTC-880 into a clinical study.