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A novel, potent dual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy.
FASEB J. 2014 Aug; 28(8):3564-78.FJ

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+Show Affiliations

Life Science Research Laboratories, Lion Corporation, Kanagawa, Japan;Department of Pharmacology, Graduate School of Dental Science, and.Taiho Pharmaceutical Corporation, Tokushima Research Planning, Tokushima, Japan.Department of Pharmacology, Graduate School of Dental Science, and.Department of Pharmacology, Graduate School of Dental Science, and.Proteolysis Research Laboratory, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; and.Taiho Pharmaceutical Corporation, Tokushima Research Planning, Tokushima, Japan.Department of Pharmacology, Graduate School of Dental Science, and.Department of Pharmacology, Graduate School of Dental Science, and Proteolysis Research Laboratory, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; and kyamamot@phar.kyushu-u.ac.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24776743

Citation

Kataoka, Shinsuke, et al. "A Novel, Potent Dual Inhibitor of Arg-gingipains and Lys-gingipain as a Promising Agent for Periodontal Disease Therapy." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 28, no. 8, 2014, pp. 3564-78.
Kataoka S, Baba A, Suda Y, et al. A novel, potent dual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy. FASEB J. 2014;28(8):3564-78.
Kataoka, S., Baba, A., Suda, Y., Takii, R., Hashimoto, M., Kawakubo, T., Asao, T., Kadowaki, T., & Yamamoto, K. (2014). A novel, potent dual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 28(8), 3564-78. https://doi.org/10.1096/fj.14-252130
Kataoka S, et al. A Novel, Potent Dual Inhibitor of Arg-gingipains and Lys-gingipain as a Promising Agent for Periodontal Disease Therapy. FASEB J. 2014;28(8):3564-78. PubMed PMID: 24776743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel, potent dual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy. AU - Kataoka,Shinsuke, AU - Baba,Atsuyo, AU - Suda,Yoshimitsu, AU - Takii,Ryosuke, AU - Hashimoto,Munetaka, AU - Kawakubo,Tomoyo, AU - Asao,Tetsuji, AU - Kadowaki,Tomoko, AU - Yamamoto,Kenji, Y1 - 2014/04/28/ PY - 2014/4/30/entrez PY - 2014/4/30/pubmed PY - 2014/10/7/medline KW - infectious diseases KW - pathogen KW - protease KW - protease inhibitor SP - 3564 EP - 78 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 28 IS - 8 N2 - 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. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/24776743/A_novel_potent_dual_inhibitor_of_Arg_gingipains_and_Lys_gingipain_as_a_promising_agent_for_periodontal_disease_therapy_ L2 - https://doi.org/10.1096/fj.14-252130 DB - PRIME DP - Unbound Medicine ER -