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Gingipains are essential to the bacterium for its virulence and survival, and development of inhibitors targeting these proteins provides an approach to treat periodontal diseases. Here, we present the first example of structure The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis , including its protease Lysine gingipain (Kgp), and their use for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimer's disease. In certain embodiments, the invention provides compounds according to Formula I, as described herein 2001-08-01 Suppression of Pathogenicity of Porphyromonas gingivalis by Newly Developed Gingipain Inhibitors Tomoko Kadowaki, Atsuyo Baba, Naoko Abe, Ryosuke Takii, Munetaka Hashimoto, Therefore, a combination of RTV and Kgp inhibitors can be used to increase plasma concentrations and brain levels of the gingipain inhibitors. As described in U.S. patent application Ser. No. 14/875,416, oral administration of RTV 15 minutes prior to the Kgp inhibitor Kyt-36 increases the half-life therefore it is expected that RTV will also increase the half-life of other Kgp inhibitors. 2003-04-01 Background Porphyromonas gingivalis and its proteolytic virulence factors lysine‐gingipain (Kgp) and arginine‐gingipain (Rgp) are emerging as major etiologic agents in the pathogenesis of Alzheimer’ Arginine gingipain is a distinct target associated with P. gingivalis that contributes to bacterial survival, replication and toxicity. An arginine gingipain inhibitor may be used as monotherapy in new indications or potentially additively with lysine gingipain inhibitors, like atuzaginstat.

Gingipain inhibitors

inhibitor of Arg-gingipains and Lys-gingipain as a promis-ing agent for periodontal disease therapy. FASEB J. 28, 3564–3578 (2014). www.fasebj.org Key Words: infectious diseases protease protease inhibitor pathogen Periodontal disease (PD) is one of the most com-mon infectious diseases in … 2004-08-01 tested potent, selective, brain-penetrant, small-molecule gingipain inhibitors in vivo. Our results indicate that small-molecule inhibi-tion of gingipains has the potential to be disease modifying in AD. AD diagnosis correlates with gingipain load in brain Tissue microarrays (TMAs) containing sex- … Gingipain R-inhibitor characterized in that it is able to specifically bind to and/or interact with D163 in the P1-pocket of gingipain R and in that it has a nitrile, diazomethlyketone, acyloxymethylketone, methlysulfonium salt, epoxysuccinyl derivative, vinylsulfone, O-acylhydroxamate, aziridine or activated disulfide group that forms a covalent, hydrolytically stabile bond to the enzyme." METHODS: OSCC cells were infected with Pg strains including gingipain mutants. To evaluate effects of inhibitors: 1) apple polyphenol (AP); 2) hop bract polyphenol (HBP); 3) high-molecular-weight fractions of HBP (HMW-HBP); 4) low-molecular-weight fractions of HBP (LMW-HBP); 5) epigallocatechin gallate (EGCg); 6) KYT-1 (Arg-gingipain inhibitor); and KYT-36 (Lys-gingipain inhibitor) in The investigators, including Stephen Dominy, MD, the chief scientific officer of Cortexyme, which has developed a gingipain inhibitor, CORE-388, identified the pathogen in the brains of patients with Alzheimer disease, as well as the organism’s gingipains—lysine-gingipain (Kgp), arginine-gingipain A (RgpA), and arginine-gingipain B (RgpB)—in the neurons of these patients. The physiological relevance of this mechanism is supported by the ability of the brain-penetrant gingipain inhibitor, COR388 (atuzaginstat), to decrease the level of LMW ApoEfragments in AD CSF after 28 days of treatment. Gingipain inhibitors may also help treat systemic disorders that are associated with periodontitis, including cardiovascular disease, rheumatoid arthritis, aspiration pneumonia, pre-term birth Total of 'gingipain r inhibitors': 7 product(s) Leupeptin .

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Phase 2/3 GAIN trial of COR388, a novel bacterial virulence factor inhibitor for Among tetracycline derivatives, the most potent gingipain inhibitor was doxycycline, followed by tetracycline and minocycline. RgpB was inhibited by doxycycline Background: Arginine-specific (RgpB and RgpA) and lysine-specific (Kgp) gingipains are secretory cysteine proteinases of Porphyromonas gingivalis that act as The Arg-gingipains, RgpA and RgpB and Lys-gingipain Kgp are secreted from P. gingivalis as inactive prodomain-bearing precursors. The amino-terminal In tissues, KLK activity is strictly controlled by a limited number of tissue-specific inhibitors, including SPINK6, an inhibitor of these proteases in skin and oral Pg's protease virulence factors known as gingipains have been identified in PD -L1 expression was measured using irreversible gingipain inhibitors against 18 Aug 2014 To date, several classes of gingipain inhibitors have been recognized. These include gingipain N-terminal prodomains, synthetic compounds, inhibitor, almost completely inhibited collagen degradation by P. gingivalis cells whereas cathepsin B inhibitor II, a Lys-gingipain inhibitor, did not.

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Reports suggest the role of Porphyromonas gingivalis specific Arg- and Secreted gingipains induce migration in human microglial cell line through PAR2 . The gingipain inhibitors, Src kinase inhibitor and β-arrestin knockdown Novel gingipain inhibitors are efficacious in treatment of periodontal disease. Phase 2/3 GAIN trial of COR388, a novel bacterial virulence factor inhibitor for Among tetracycline derivatives, the most potent gingipain inhibitor was doxycycline, followed by tetracycline and minocycline. RgpB was inhibited by doxycycline Background: Arginine-specific (RgpB and RgpA) and lysine-specific (Kgp) gingipains are secretory cysteine proteinases of Porphyromonas gingivalis that act as The Arg-gingipains, RgpA and RgpB and Lys-gingipain Kgp are secreted from P. gingivalis as inactive prodomain-bearing precursors. The amino-terminal In tissues, KLK activity is strictly controlled by a limited number of tissue-specific inhibitors, including SPINK6, an inhibitor of these proteases in skin and oral Pg's protease virulence factors known as gingipains have been identified in PD -L1 expression was measured using irreversible gingipain inhibitors against 18 Aug 2014 To date, several classes of gingipain inhibitors have been recognized. These include gingipain N-terminal prodomains, synthetic compounds, inhibitor, almost completely inhibited collagen degradation by P. gingivalis cells whereas cathepsin B inhibitor II, a Lys-gingipain inhibitor, did not.

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 Arg-gingipains (Rgps) and Lys-gingipain (Kgp) are cysteine proteinases secreted by Porphyromonas gingivalis, the major pathogen implicated in periodontal disease. Gingipains are essential to the bacterium for its virulence and survival, and development of inhibitors targeting these proteins provides an approach to treat periodontal diseases. Here, we present the first example of structure inhibitors. Adding the inhibitors to CDM containing albumin revealed that leupeptin (Arg-gingipain A and B inhibitor) was more efﬁcient at inhibiting growth than cathepsin B inhibitor II (Lys-gingipain inhibitor).
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An arginine gingipain inhibitor may be used as monotherapy Arginine gingipain is a distinct target associated with P. gingivalis that contributes to bacterial survival, replication and toxicity. An arginine gingipain inhibitor may be used as monotherapy in new indications or potentially additively with lysine gingipain inhibitors, like atuzaginstat.

It is, therefore, suggested that gingipain inhibition by vaccination and gingipain-specific inhibitors is a useful therapy for adult periodontitis caused by P. gingivalis infection.
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CIRC del 2 2006 - 2008.pdf - Linköping University

Our results indicate that small-molecule inhibi-tion of gingipains has the potential to be disease modifying in AD. AD diagnosis correlates with gingipain load in brain Tissue microarrays (TMAs) containing sex- and age-matched brain Suppression of Pathogenicity of Porphyromonas gingivalis by Newly Developed Gingipain Inhibitors Tomoko Kadowaki, Atsuyo Baba, Naoko Abe, Ryosuke Takii, Munetaka Hashimoto, The critical role of proteinases in the growth of P. gingivalis was further investigated using specific Arg- and Lys-gingipain inhibitors. Adding the inhibitors to CDM containing albumin revealed that leupeptin (Arg-gingipain A and B inhibitor) was more efficient at inhibiting growth than cathepsin B inhibitor II (Lys-gingipain inhibitor). Class-specific inhibitors and gingipain-null mutants showed that gingipains were the only enzymes responsible for this activity. The kinetic constants obtained for Rgps were comparable to those of human aminopeptidases but Kgp aminopeptidase activity was weaker. Therefore, a combination of RTV and Kgp inhibitors can be used to increase plasma concentrations and brain levels of the gingipain inhibitors.

PDF Cellular and molecular responses of periodontal

The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis , including its protease Lysine gingipain (Kgp), and their use for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimers disease. The third Cortexyme presentation, titled “COR388 (atuzaginstat), a novel gingipain inhibitor, decreases ApoE fragmentation in the CNS of Alzheimer’s disease patients” (Abstract 40578P3), presents data indicating P. gingivalis gingipains target and cleave ApoE proteins in the nervous system of AD patients. Specifically, the gingipain inhibitor reduced deposits of lipids in the aortas of infected animals and prevented the progression of atherosclerosis linked to P. gingivalis infection. A lysine gingipain inhibitor of the invention can be administered in the same composition as an additional therapeutically active agent. Alternatively, the additional therapeutically active agent can be administered separately before, concurrently with, or after administration of the lysine gingipain inhibitor.

At the minimal concentration of 17.826 μM, inhibition up to 98.7% and 89.4% was noted for gingipain R and K respectively. of inhibitors that could be used for the treatment of periodontitis.