| Co-Investigator(Kenkyū-buntansha) |
浅尾 哲次 大鵬薬品工業株式会社, 創薬センター合成研究所, 所長(研究職)
AKAMINE Akifumi KYUSHU UNIVERSITY, GRADUATE SCHOOL OF DENTAL SCIENCE, PROFESSOR, 大学院・歯学研究院, 教授 (00117053)
NAKANISHI Hiroshi KYUSHU UNIVERSITY, GRADUATE SCHOOL OF DENTAL SCIENCE, PROFESSOR, 大学院・歯学研究院, 教授 (20155774)
TETSUJI Asao TAIHO PHARMACEUTICAL CO., LTD., DIRECTOR
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| Research Abstract |
The black-pigmented, Gram-negative anaerobic bacterium Porphyromonas gingivalis is widely implicated as an important etiologic agent in certain forms of periodontitis, particularly adult periodontitis in humans. The virulence factors of P.gingivalis have been studied in some detail. These include fimbriae, lectin-type adhesions, lipopolysaccharide, hemagglutinins, and various hydrolytic enzymes. Among these, proteolytic enzymes may play a crucial role in P.gingivalis virulence, since they have the ability to degrade host tissues and immune response mediators, cellular constituents, and adhesion molecules that promote colonization. In addition, these enzymes may be crucial for providing heme and amino acids that are essential for the growth and proliferation of this asaccharolytic organism. Arg-gingipain (Rgp) and Lys-gingipain (Kgp) are two major cysteine proteinases produced by P.gingivalis. Both gingipains have been shown to be responsible for a wide range of pathologies of adult typ
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e periodontitis in terms of destruction of the the host periodontal tissues and disruption of host defense mechanisms. Therefore, it is likely that P.gingivalis virulence can be attenuated by inhibition of gingipains with proteinase inhibitors. In the present study, we discovered new agents inhibiting the Rgp activity. The natural inhibitor FA-70C1 was isolated from the culture medium of Streptomyces FA-70 strain. The molecular formula of this compound was C_<27>H_<43>N_9O_7 and its molecular mass was 606. This inhibitor strongly inhibited Rgp and exhibited the weak inhibitory activity toward the host tissue-derived cysteine proteinases cathepsins B, L, K, and S.We also designed and synthesized the oligopeptides inhibiting the Rgp activity. The most potent synthetic peptide (KYT-1) had the strong inhibitory activity on Rgp (IC50, 10^<-8> M) but not cathepsins. The degradation of human type I collagen and immunogrobulins by Rgp was strongly suppressed by FA-70C1 and KYT-1. These inhibitors inhibited the Rgp-induced disruption of human gingival fibroblasts. These results suggest that the present inhibitors are valuable agents for attenuation of P.gingivalis virulence. Less
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