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

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.

• Authors: Shinsuke Kataoka, Atsuyo Baba, Yoshimitsu Suda, Ryosuke Takii, Munetaka Hashimoto, Tomoyo Kawakubo, Tetsuji Asao, Tomoko Kadowaki, Kenji Yamamoto
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 28 Issue 8 Pg. 3564-78 (Aug 2014) ISSN: 1530-6860 [Electronic] United States
• PMID: 24776743 (Publication Type: Journal Article)
• Copyright: © FASEB.

Chemical References

• Adhesins, Bacterial
• Culture Media, Conditioned
• Cysteine Proteinase Inhibitors
• Cytokines
• Gingipain Cysteine Endopeptidases
• Oligopeptides
• carbobenzoxy-Glu-Lys-CO-Arg-CO-NH(CH2)2Ph
• Cysteine Endopeptidases

Topics

• Adhesins, Bacterial (drug effects)
• Animals
• Capillary Permeability (drug effects)
• Cell Adhesion (drug effects)
• Culture Media, Conditioned (pharmacology, toxicity)
• Cysteine Endopeptidases (drug effects)
• Cysteine Proteinase Inhibitors (pharmacology, therapeutic use)
• Cytokines (metabolism)
• Disease Progression
• Dogs
• Drug Evaluation, Preclinical
• Fibroblasts (cytology, drug effects, enzymology)
• Gingipain Cysteine Endopeptidases
• Guinea Pigs
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, enzymology)
• Humans
• Oligopeptides (chemical synthesis, pharmacology, therapeutic use)
• Periodontitis (drug therapy, microbiology)
• Porphyromonas gingivalis (enzymology, pathogenicity)
• Proteolysis
• Substrate Specificity
• Virulence