2004-08-01

1 INTRODUCTION. COR388 is an irreversible active‐site inhibitor developed to target lysine‐gingipain (Kgp) in the brain of Alzheimer's disease (AD) patients. 1 Kgp is a cysteine protease virulence factor secreted by Porphyromonas gingivalis, a keystone bacterium in the development of periodontal disease. 2 The secretion of gingipain proteases is part of the asaccharolytic metabolism of P

Limonianin, inhibited biofilm growth and gingipain activity of P. gingivalis [21]. Similarly, a number of prenylated flavonoids derived from the Epimedium species also inhibited gingipain activity and hindered P. gingivalis growth and biofilm formation [21]. Morus … 2019-03-20 2019-01-01 Gingipain inhibitors Three pairs of inhibitors of Rgp and Kgp were compared: leupeptin and cathepsin B inhibitor II, KYT‐1 and KYT‐36, and PPACK and Z‐FK‐ck. The cysteine protease inhibitor E64 was also tested. Leupeptin is a bacterial product that inhibits many serine, threonine, and cysteine proteases (Bogyo & Wang, 2002). In some embodiments, compounds of the invention can be administered with natural gingipain inhibitors including melabaricone C, isolated from nutmeg or polyphenolic compounds derived from plants, such as cranberry, green tea, apple, and hops can be administered in … 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 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. Gingipains degrade a broad range of proteins (e.g., immunoglobulins, proteinase inhibitors, actin, and collagen) which can lead to cytoskeleton collapse and apoptosis in many types of cells.

The GAIN (GingipAIN Inhibitor for Treatment of Alzheimer’s Disease) Trial is based on a growing body of scientific evidence that the bacteria P. gingivalis, most commonly associated with degenerative gum disease, can infect the brain and cause Alzheimer’s disease. 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. 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. The GAIN Trial (GingiPAIN inhibitor for treatment of Alzheimer’s disease) is a pivotal Phase 2/3 randomized, double-blind, placebo-controlled study that is assessing the efficacy, safety, and tolerability of two dose levels of COR388 oral capsules in subjects with mild to moderate Alzheimer’s disease. of inhibitors that could be used for the treatment of periodontitis. To develop successful therapeutic gingipain inhibitors, the gingipain chiefly responsible for the virulence of P. gingivalis must be clearly identified. Reynolds et al.

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).

Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae,typicallyassociatedwithperi- 2021-01-26 2004-12-01 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. J Periodontol 2003;74:111‐118.

Limonianin, inhibited biofilm growth and gingipain activity of P. gingivalis [21]. Similarly, a number of prenylated flavonoids derived from the Epimedium species also inhibited gingipain activity and hindered P. gingivalis growth and biofilm formation [21]. Morus …

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. COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients - Raha - 2020 - Alzheimer's & Dementia - Wiley Online Library Skip to Article Content Skip to Article Information Search withinThis JournalALZ JournalsWiley Online Library Gingipain inhibition reduced the bacterial load of an established P. gingivalisbrain infection, blocked Aβ1-42production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalisbrain colonization and neurodegeneration in Alzheimer's disease. Furthermore, KYT-36, in conjunction with KYT-1, a specific inhibitor of arg-specific gingipains, abolished P. gingivalis co-aggregation, hemagglutinating activity, proteolytic activity on various host proteins and the bacterium’s ability to disrupt neutrophil bactericidal activity and fibroblast adherence. In mice, small-molecule gingipain inhibitors ameliorate infection, reduce Aβ42 peptide production and neuroinflammation, and protect neurons from gingipain toxicity. The company has completed Phase 1 clinical trials of their gingipain inhibitor COR388 , and will run a Phase 2/3 study to determine if it can improve cognition in people with mild to moderate AD, Lynch told Alzforum. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus.

Dual action of bacteriocin PLNC8 αβ through inhibition of Porphyromonas gingivalis Har demenspatienter med högre gingipain-aktivitet i cerebrospinalvätska for disease causation and treatment with small-molecule inhibitors. virulensfaktor, arginin gingipain typ B (RgpB), har rapporterats toid arthritis in patients treated with or without tumor necrosis factor inhibitors. J Periodontol. more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study. Demirel I, Bengtsson T, Karlsson H. Lipoprotein modifications by gingipains of Lipoprotein modifications by gingipains of Porphyromonas gingivalis subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study.
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Demirel I, Bengtsson T, Karlsson H. Lipoprotein modifications by gingipains of Lipoprotein modifications by gingipains of Porphyromonas gingivalis subclasses more efficiently compared to the PCSK9 inhibitor evolocumab, a pilot study. Green tea inhibits proteolytic enzymes in GCF from patients with chronic periodontitis The role of gingipains in the pathogenesis of periodontal disease.

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. COR388 is an irreversible active‐site inhibitor developed to target lysine‐gingipain (Kgp) in the brain of Alzheimer's disease (AD) patients. 1 Kgp is a cysteine protease virulence factor secreted by Porphyromonas gingivalis, a keystone bacterium in the development of periodontal disease.
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Furthermore, KYT-36, in conjunction with KYT-1, a specific inhibitor of arg-specific gingipains, abolished P. gingivalis co-aggregation, hemagglutinating activity, proteolytic activity on various host proteins and the bacterium’s ability to disrupt neutrophil bactericidal activity and fibroblast adherence.

The proliferation was sustained inhibitor of Arg-gingipains and Lys-gingipain as a promis- ing agent for periodontal effects of such inhibitors on host proteases, it is very important for us to Periodontitis is a biofilm-associated irreversible inflammation of the periodontal tissues. Reports suggest the role of Porphyromonas gingivalis specific Arg- and Secreted gingipains induce migration in human microglial cell line through PAR2 .

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In a 28‐day dose‐response study, COR388 inhibited the lysine‐gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology.

Different concentrations of gingipains significantly promoted the proliferation of RASMCs, except those treated with 1 μg/mL, compared to the untreated controls.