Inhibitors of the cell-surface proteinases of the periodontal pathogen Porphyromonas gingivalis

Porphyromonas gingivalis is a major pathogen associated with chronic periodontitis. Major virulence factors of this organism are its cell-surface located cysteine proteinases known as gingipains that include the Arg-specific proteinases RgpA, RgpB and the Lys-specific proteinase Kgp. The gingipains have been demonstrated to be essential for the virulence of the organism in animal models of disease. Hence there is considerable interest in the development of specific inhibitors of these proteinases that would be safe for human use. Review of the reported peptide-derived and non-peptide inhibitors of the gingipains reveals a surprising diversity of affinity, specificity and structural features. The ability of the gingipain active site to accommodate various substrates makes structure-based drug design of high specificity inhibitors a challenge. Here, we summarize the structural diversity of known gingipain substrates and inhibitors, including those derived from bovine milk and the gingipain propeptides. Inhibition of the gingipains using these peptides has been shown to reduce bacterial growth, disrupt biofilm development and significantly reduce lesion development in an animal model of infection. Hence these inhibitors may have potential to develop as therapeutics for P. gingivalis-associated periodontitis.