A novel, potentdual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy

Shinsuke Kataoka, Atsuyo Baba, Yoshimitsu Suda, Ryosuke Takii, Munetaka Hashimoto, Tomoyo Kawakubo, Tetsuji Asao, Tomoko Kadowaki, Kenji Yamamoto

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys-gingipain (Kgp). Growing evidence indicates that these 2 types of gingipains synergistically contribute to the entire virulence of the organism and increase the risk of periodontal disease (PD) by disrupting the host immune system and degrading the host tissue and plasma proteins. Therefore, a dual inhibitor of both gingipains would have attractive clinical potential for PD therapy. In this study, a novel, potent, dual inhibitor of Rgp and Kgp was developed through structure-based drug design, and its biological potency was evaluated in vitro and in vivo. This inhibitor had low nanomolar inhibitory potency (Ki=40 nM for Rgp, Ki=0.27 nM for Kgp) and good selectivity for host proteases and exhibited potent antibacterial activity against P. gingivalis by abrogating its manifold pathophysiological functions. The therapeutic potential of this inhibitor in vivo was also verified by suppressing the vascular permeability that was enhanced in guinea pigs by the organism and the gingival inflammation in beagle dog PD models. These findings suggest that a dual inhibitor of Rgp and Kgp would exhibit noteworthy anti-inflammatory activity in the treatment of PD.

Original languageEnglish
Pages (from-to)3564-3578
Number of pages15
JournalFASEB Journal
Volume28
Issue number8
DOIs
Publication statusPublished - Aug 2014

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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