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Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan (T.K., A.B., N.A., R.T., M.H., T.T., K.Y.); and Taiho Pharmaceutical Co. Ltd., Research Center, Saitama, Japan (S.O., Y.S., T.A.)
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 analogs able to inhibit either Rgp or Kgp, which are synthesized on the basis of the cleavage site specificity of human salivary histatins by each enzyme. Among this series of compounds, carbobenzoxy-Lys-Arg-CO-Lys-N-(CH3)2 (KYT-1) and carbobenzoxy-Glu(NHN(CH3)Ph)-Lys-CO-NHCH2Ph (KYT-36) were found to be the most potent inhibitors of Rgp and Kgp, respectively, with Ki values of 10-11 to 10-10 M order. Both inhibitors exhibited slight or no inhibition on mammalian proteinases such as trypsin and cathepsins B, L, and H. All of the virulence induced by the culture supernatant of P. gingivalis tested, including the 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 both should provide a broader application in studies of this important class of enzymes and facilitate the development of new approaches to periodontal diseases.
Address correspondence to:Dr. Kenji Yamamoto, Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: kyama{at}dent.kyushu-u.ac.jp
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