Lysine-specific gingipain K (Kgp)

Lysine-specific gingipain K (Kgp) is a potent cysteine protease secreted by the anaerobic bacterium Porphyromonas gingivalis, which is recognized as a keystone pathogen in the development of chronic periodontitis (Potempa et al., 2003). Kgp specifically hydrolyzes peptide bonds at the C-terminal side of lysine residues, a function essential for the bacterium's survival as it facilitates the acquisition of nutrients, such as heme and amino acids, from host proteins (UniProt P95453). Beyond oral pathology, Kgp has gained significant attention as a therapeutic target for Alzheimer's disease following the discovery of the enzyme and P. gingivalis DNA in the brains of patients (Dominy et al., 2019). In the central nervous system, Kgp is hypothesized to drive neurodegeneration through the cleavage of tau and other neuronal proteins, contributing to neuroinflammation (Dominy et al., 2019). Small-molecule inhibitors like atuzaginstat (COR388) have been developed to block Kgp activity, aiming to reduce neuroinflammation and cognitive decline (Cortexyme, 2021). Although recent clinical trials for Alzheimer's disease have faced challenges regarding efficacy and safety, Kgp remains a focal point for research into the systemic links between periodontal infection and chronic inflammatory diseases. Therapeutic strategies targeting Kgp involve highly specific inhibitors designed to minimize off-target effects on human proteases while effectively reducing bacterial virulence.

Other names

Gingipain KLys-gingipainLysine-specific cysteine proteinaseKGP

Small molecule inhibition of the cysteine protease activity of Kgp, preventing the cleavage of host proteins and reducing bacterial virulence and survival.