IADR Abstract Archives
Novel Gingipain Inhibitors are Efficacious in Treatment of Periodontal Disease
Objectives: Gingipains are cysteine proteases that are the major virulence factors of Porphyromonas gingivalis (Pg), a keystone pathogen in the development of periodontal disease (PD). Highly potent and selective small-molecule gingipain inhibitors with brain penetration were developed with oral bioavailability for the treatment of Alzheimer’s disease (AD). Here, gingipain inhibitors were tested in a mouse model of Pg-induced PD and in dogs with natural PD.
Methods: Mice were orally infected with Pg for 42 days and treated from day 35 through day 70 with vehicle or active drug including moxifloxacin, arginine-gingipain inhibitor COR286, lysine-gingipain inhibitors COR271 or COR388, and combinations of these treatments.
Studies were next conducted in aged dogs with natural PD. A similar bacterial species to Pg, P. gulae, is present in dogs and secretes gingipains. COR388 10 mg/kg was administered daily for 14 days, and in a second study, COR388 0.5 mg/kg was administered BID for 90 days.
Results: In mice, all COR271 treated arms demonstrated recovery of bone loss when compared to bone loss at day 35 of infection, as well as a significant difference when compared to vehicle treated mice at day 70. The second lysine-gingipain inhibitor, COR388, demonstrated significant beneficial effects on bone loss similar to COR271.
In dogs, COR388 10 mg/kg administered daily for 14 days completely suppressed lysine-gingipain activity in oral plaque and reduced bacterial load in saliva. COR388 0.5 mg/kg administered BID for 90 days showed improvement in PD pathology as measured by a reduction in diseased-pocket depths compared to placebo.
Conclusions: Brain-penetrant lysine-gingipain inhibitors, including COR271 and COR388, designed for the treatment of AD, were effective in reversing alveolar bone loss in mice after oral Pg infection, and COR388 reduced bacterial load and pocket depth in aged dogs with natural PD. COR388 is currently the subject of the GAIN trial in AD, which includes a sub-study to investigate exploratory periodontal endpoints. A peripherally focused lysine-gingipain inhibitor is progressing through IND-enabling studies to target peripheral Pg infections such as PD.
Methods: Mice were orally infected with Pg for 42 days and treated from day 35 through day 70 with vehicle or active drug including moxifloxacin, arginine-gingipain inhibitor COR286, lysine-gingipain inhibitors COR271 or COR388, and combinations of these treatments.
Studies were next conducted in aged dogs with natural PD. A similar bacterial species to Pg, P. gulae, is present in dogs and secretes gingipains. COR388 10 mg/kg was administered daily for 14 days, and in a second study, COR388 0.5 mg/kg was administered BID for 90 days.
Results: In mice, all COR271 treated arms demonstrated recovery of bone loss when compared to bone loss at day 35 of infection, as well as a significant difference when compared to vehicle treated mice at day 70. The second lysine-gingipain inhibitor, COR388, demonstrated significant beneficial effects on bone loss similar to COR271.
In dogs, COR388 10 mg/kg administered daily for 14 days completely suppressed lysine-gingipain activity in oral plaque and reduced bacterial load in saliva. COR388 0.5 mg/kg administered BID for 90 days showed improvement in PD pathology as measured by a reduction in diseased-pocket depths compared to placebo.
Conclusions: Brain-penetrant lysine-gingipain inhibitors, including COR271 and COR388, designed for the treatment of AD, were effective in reversing alveolar bone loss in mice after oral Pg infection, and COR388 reduced bacterial load and pocket depth in aged dogs with natural PD. COR388 is currently the subject of the GAIN trial in AD, which includes a sub-study to investigate exploratory periodontal endpoints. A peripherally focused lysine-gingipain inhibitor is progressing through IND-enabling studies to target peripheral Pg infections such as PD.