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Received for publication June 30, 2004.
Revised August 20, 2004.
Accepted for publication September 9, 2004.
Arg-gingipain (Rgp) and Lys-gingipain (Kgp) are cysteine proteinases produced by Porphyromonas gingivalis, a major etiological bacterium of periodontal diseases. Here we show a series of small peptide analogues able to inhibit either Rgp or Kgp which are synthesized based on the cleavage site specificity of human salivary histatins by each enzyme. Among this series of compounds, KYT-1 and KYT-36 were found to be the most potent inhibitors of Rgp and Kgp, respectively, with Ki value of 10-11-10-10 M order. Both inhibitors exhibited slight or no inhibition on mammalian proteinases such as trypsin and cathepsins B, L, and H. All the virulence induced by the culture supernatant of P. gingivalis tested, including degradation of various host proteins such as human type I collagen, immunoglobulins, fibronectin and fibrinogen, disruption of the bactericidal activity of polymorphonuclear leukocytes, and enhancement of the vascular permeability, were strongly inhibited by a combined action of both inhibitors. The functions essential for the bacterium to grow and survive in the periodontal pocket, such as coaggregation and acquisition of amino acids, were also strongly inhibited by the combined action of both inhibitors. The disruption of the adhesion and viability of human fibroblasts and hemagglutination by the organism were strongly suppressed by a single use of KYT-1. These results thus indicate that the newly developed KYT-1 and KYT-36 should both provide a broader application in studies of this important class of enzymes and facilitate the development of new approaches to periodontal diseases.
Key words:
Combinatorial chemistry, Antibiotic mechanisms
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