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GAIN Trial: A Randomized, Double-Blind, Placebo-Controlled Study of COR388 in Subjects With Alzheimer's Disease: Actual Study Start Date : March 28, 2019: Estimated Primary Completion Date : December 31, 2021: Estimated Study Completion Date : December 31, 2022 Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD. 1 INTRODUCTION Over the past 15 years a possible association between Alzheimer disease (AD) and periodontitis has emerged. We identified the bacterial pathogen, Porphyromonas gingivalis(Pg), and its protease virulence factors, gingipains, in the brain of patients with Alzheimer’s disease (AD). Gingipain levels in AD brains were shown to significantly correlate with AD diagnosis and tau and ubiquitin pathology. Gingipains are the major virulence factors of Porphyromonas gingivalis, the main periodontopathogen. It is expected that inhibition of gingipain activity in vivo could prevent or slow down the Remember, gingipains are proteases, meaning they like to chop up proteins.

At the minimal concentration of 17.826 μM, inhibition up to 98.7% and 89.4% was noted for gingipain R and K respectively. The data was also supported by the in silico docking experiments which revealed high exothermic enthalpies (−7.01 and −7.02 cal mol −1 ). 23 Jan 2019 Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ 1–42 production, reduced with various neuropathological hallmarks of Alzheimer's disease. Oral administration of gingipain inhibitors to mice with established brain infections decreases 15 Jun 2020 gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer's disease (AD). In a recent study we 28 Jul 2020 gingivalis in Alzheimer's disease and, in turn, the therapeutic potential for the gingipain inhibitor atuzaginstat in treating and preventing bodies or its production by the BACE inhibitors [54, 55].

Alternatively, the additional therapeutically active agent can be administered separately before, concurrently with, or after administration of the lysine gingipain inhibitor.

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People with Alzheimer’s disease have elevated levels of the bacterial protease gingipain in their brain tissue, they find. In mice, small-molecule gingipain inhibitors ameliorate infection, reduce Aβ42 peptide production and neuroinflammation, and protect neurons from gingipain toxicity. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ 1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus.

Avdelningen för klinisk kemi och farmakologi

They made some that block Kgp and some that block Rgp. When they infected cells of the same SH-SY5Y cell line they used before with P. gingivalis, about half of the cells died. Giving the cells the One of the cohorts enrolled 9 Alzheimer’s disease patients, and 6 of these patients received the small-molecule gingipain inhibitor called COR388.

Interestingly, the recombinant viral caspase inhibitors, CrmA, in which the reactive site Asp was replaced by Lys (k ass =1.4×10 5 M −1 s −1) and wild-type p35 (K i =2×10 −10 M), are surprisingly strong inhibitors of gingipain K [20]. Finally, Kgp was inhibited by human salivary histatin 5 (EC 50 =1.4×10 5 M) [21].
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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. 2019-03-20 · Structural determinants of inhibition of Porphyromonas gingivalis gingipain K by KYT-36, a potent, selective, and bioavailable peptidase inhibitor A bacteria that causes gum disease has been linked to Alzheimer's disease in a study scientists believe could pave the way for new or a form of the gingipains enzyme known as arginine-gingipain. Interestingly, the recombinant viral caspase inhibitors, CrmA, in which the reactive site Asp was replaced by Lys (k ass =1.4×10 5 M −1 s −1) and wild-type p35 (K i =2×10 −10 M), are surprisingly strong inhibitors of gingipain K [20]. Finally, Kgp was inhibited by human salivary histatin 5 (EC 50 =1.4×10 5 M) [21].

for disease causation and treatment with small-molecule inhibitors. 12 Jan 2021 To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the 20 Mar 2021 Keywords: Alzheimer's disease; dementia; beta-amyloid; germ theory; drug hippocampal cells, suggesting that gingipain inhibitors could 26 May 2020 In 2019, 5.8 million Americans were living with Alzheimer's disease (AD), at a cost to Gingipain Inhibitor May Reduce P. gingivalis Infection. 28 Jan 2021 P. gingivalis DNA has been detected in Alzheimer disease brain autopsy Gingipain inhibition also reduced the P. gingivalis load and Keywords: Gut microbiota, Oral microbiota, Alzheimer disease.
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Torbjörn Bengtsson - School of Medical Sciences - Örebro

Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ 1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease. 2019-2-27 2019-1-1 Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD. 1 INTRODUCTION Over the past 15 years a possible association between Alzheimer disease (AD) and periodontitis has emerged. In a poster titled “Comprehensive Alzheimer’s pathology is induced by Porphyromonas gingivalis infection: atuzaginstat (COR388) and other proprietary gingipain inhibitors protect against synaptic 2021-3-27 · 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 … 2021-1-12 Our data suggest that gingipain proteases may mediate ApoE proteolysis in the brain, with higher susceptibility of ApoE4, providing a link between P. gingivalis infection and the APOE4 allele, a major risk factor in AD. Based on the literature, fragmentation of ApoE4 by gingipains would be likely to reduce synaptic maintenance and regulation of immune response as well as aggravate toxicity to cells … Gingipains are the major virulence factors of Porphyromonas gingivalis, the main periodontopathogen. It is expected that inhibition of gingipain activity in vivo could prevent or slow down the 2019-12-16 · COR388, A NOVEL GINGIPAIN INHIBITOR, DECREASES FRAGMENTATION OF APOE IN ALZHEIMER’S DISEASE CENTRAL NERVOUS SYSTEM CTAD 2019 Michael J. Detke, M.D., Ph.D. Gingipain Inhibitor May Reduce P. gingivalis Infection The researchers say that the study also provides “a new conceptual framework for disease treatment.” They designed and synthesized small-molecule inhibitors targeting gingipains, which consist of lysine-gingipain (Kgp), arginine-gingipain A (RgpA) and arginine-gingipain B (RgpB), and COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory end-points in periodontal disease.