Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that is implicated as a major etiologic agent of adult
periodontal disease. This bacterium is asaccharolytic and possesses strong potency for proteolysis. It produces a novel class of
cysteine proteinases, termed
gingipains, in the cell-associated and secretory forms.
Gingipains consist of
arginine-X-specific
cysteine proteinases (Arg-
gingipains, Rgps) and
lysine-X-specific
cysteine proteinase (
Lys-gingipain, Kgp). Previous studies using various P. gingivalis mutants deficient in Rgp- and/or Kgp-encoding genes have revealed that both
enzymes are important for the bacterium both to exhibit its virulence and to survive in
periodontal pockets. Mammalian internal
proteinase inhibitors such as
cystatins, a1-antichymotrypsin, and
tissue inhibitor of metalloproteinases (TIMPs) have little or no effects on the proteolytic activities of these
enzymes, suggesting the evasion of the bacterium from host defense mechanisms. Recent epidemiological reports have shown a significant relation between
periodontal diseases and systemic diseases such as
cardiovascular diseases and diabetes. Thus, the development of potent inhibitors specific for
gingipains provides new therapeutic approaches to treat
periodontal diseases and the related systemic diseases. More recently, we have developed novel synthetic inhibitors specific for Rgp and Kgp, based on the specificity and efficacy of cleavage of
histatins by each
enzyme. We have also isolated a novel and potent inhibitor of Rgp from the culture supernatant of Streptomyces species strain
FA-70, now designated as
FA-70C1. Here we summarized the usefulness of these new inhibitors in providing a broader application in studies of this important class of
enzymes.