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- | atuzaginstat (COR388) / Lighthouse Pharma
Journal: Porphyromonas gingivalis, neuroinflammation and Alzheimer's disease. (Pubmed Central) - Jan 24, 2024
production, ApoE proteolysis, and reduced neuroinflammation. In addition, therapeutic compounds like COR388 and COR286, as gingipain inhibitors, prevent P. gingivalis colonization in the brain and have a beneficial action in some conditions like aspiration pneumonia, low birth rate, rheumatoid arthritis, PerioD and AD.
- | Journal: Molecular docking analysis of imidazole quinolines with gingipain R from Porphyromonas gingivalis. (Pubmed Central) - Sep 18, 2023
In this research we aim to target the gingipain R protein with imidazole quinoline derivatives (1-6) via insilico means. Molecular docking results show, compounds (1-6) have better affinity and amino acid interactions compared to the standard clinically proven drugs used as control group, and they obey Lipinski's rule of five and can be used as potential drug candidates to inhibit gingipain R.
- atuzaginstat (COR388) / Lighthouse Pharma
The gingipain inhibitor atuzaginstat and results of the GAIN trial (In-Person) - Jul 6, 2023 - Abstract #AAIC2023AAIC_6178;
Since the patients most likely to benefit from the results of the clinical trials underway are those with mild-to-moderate AD, more studies are being planned. Atuzaginstat can address the ongoing need for treatment for most patients for whom anti-amyloids are not suitable.
- LHP588 / Lighthouse Pharma
Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP588, A Second-Generation Gingipain Inhibitor for the Treatment of P. Gingivalis - Positive Alzheimer Dementia (In-Person) - Jul 6, 2023 - Abstract #AAIC2023AAIC_2469;
Conclusion : LHP588 was well-tolerated in healthy volunteers without evidence of hepatic safety signals to date, and its PK profile was supportive of once daily dosing. The Phase 2 trial of LHP588 proposed to start in late 2023 will be similar in design to the prior atuzaginstat study but will be restricted to subjects with Pg + saliva.
- atuzaginstat (COR388) / Quince Therap
Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP88, a Second-Generation Gingipain Inhibitor for the Treatment of P. Gingivalis-Associated Dementia (Salon 3) - May 9, 2023 - Abstract #ASCP2023ASCP_374;
Chronic toxicology and rodent metabolite studies are also supportive of safety and progression to Phase 2. Clinical results with the first generation gingipain inhibitor atuzaginstat informed the new study design for precision enrollment and efficacious exposures.
- atuzaginstat (COR388) / Quince Therap
Phase 2 Study Design and New Data from the Phase 1 SAD/MAD Trial of LHP88, a Second-Generation Gingipain Inhibitor for the Treatment of P. Gingivalis-Associated Dementia (Salon 4) - Apr 15, 2023 - Abstract #ASCP2023ASCP_243;
Chronic toxicology and rodent metabolite studies are also supportive of safety and progression to Phase 2. Clinical results with the first generation gingipain inhibitor atuzaginstat informed the new study design for precision enrollment and efficacious exposures.
- | Journal: Dysregulation of Stress-Induced Translational Control by Porphyromonas gingivalis in Host Cells. (Pubmed Central) - Mar 30, 2023
The effects of gingipain inhibitors and gingipain-deficient P. gingivalis mutants confirmed these pathogen-specific proteases as the effector of exacerbated translational repression. Gingipains are known to degrade the mammalian target of rapamycin (mTOR) and the findings of this study implicate the gingipain-mTOR axis as the effector of host translational dysregulation during stress.
- |||| Clinical: PSG members Hubert Fernandez, @BrundinPatrik Eric Macklin, @ZoltanMari, Andrew Siderowf are collectively eager to further understand the mechanism of gingipain inhibition and its potential to improve the lives of patients suffering from Parkinson’s disease https://t.co/0zcZcthfhB (Twitter) - Feb 25, 2023
- | atuzaginstat (COR388) / Cortexyme
Journal: COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease. (Pubmed Central) - Oct 19, 2022
gingivalis is opsonized by Aβ42, is capable of entering the brain, and is an accelerant of neuropathologies in rodent models of AD. Thus, in our opinion, this bacteria is highly likely to be a pathogen capable of initiating or precipitating the progression of AD, which agrees with the pathogen hypothesis of clinical AD development.
- | Journal: Porphyromonas gingivalis outer membrane vesicles modulate cytokine and chemokine production by gingipain-dependent mechanisms in human macrophages. (Pubmed Central) - Jun 15, 2022
Thus, in our opinion, this bacteria is highly likely to be a pathogen capable of initiating or precipitating the progression of AD, which agrees with the pathogen hypothesis of clinical AD development. outer membrane vesicles may play a dual role during P. gingivalis infection based on their ability to induce changes in the immune responses of human macrophages, probably via gingipain-dependent events.
- | Journal: Dual Inhibitory Activity of Petroselinic Acid Enriched in Fennel Against Porphyromonas gingivalis. (Pubmed Central) - Jun 8, 2022
Taken together, our findings suggest clinical applicability of HEF and petroselinic acid for periodontitis therapy to eliminate P. gingivalis and its major virulence factors on the basis of the dual anti-P. gingivalis activity, i.e., rapid bacteriolysis and gingipain inhibition.
- | Journal: Secreted gingipains from Porphyromonas gingivalis increase permeability in human cerebral microvascular endothelial cells through intracellular degradation of tight junction proteins. (Pubmed Central) - Apr 8, 2022
Furthermore, intracellular localization of outer membrane vesicles (OMVs) bound gingipains from WT P. gingivalis and OMV-induced degradation of ZO-1 and occludin were also observed in hCMEC/D3 cells. Thus, the delivery of gingipains into the cerebral microvascular endothelial cells, probably through OMV, may be responsible for the BBB damage through intracellular degradation of ZO-1 and occludin.
- | Journal: Porphyromonas gingivalis Gingipains Induce Cyclooxygenase-2 Expression and Prostaglandin E Production via ERK1/2-Activated AP-1 (c-Jun/c-Fos) and IKK/NF-κB p65 Cascades. (Pubmed Central) - Mar 8, 2022
Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.
- | Journal: Microglial cathepsin B and Porphyromonas gingivalis gingipains as potential therapeutic targets for sporadic Alzheimer's disease. (Pubmed Central) - Nov 4, 2021
Furthermore, orally bioavailable and brain-permeable inhibitor of gingipain is now being tested in AD patients. It is largely expected that clinical studies countering bacterial virulence factors may pave the way to establish the prevention and early treatment of AD.
- | Journal: Regulation of olfactomedin 4 by Porphyromonas gingivalis in a community context. (Pubmed Central) - Sep 24, 2021
The results establish a novel mechanism by which P. gingivalis modulates epithelial cell function which is dependent on community context. These interrelationships have relevance for innate inflammatory responses and epithelial cell fate decisions in oral health and disease.
- | Journal: Secreted gingipains from Porphyromonas gingivalis induce microglia migration through endosomal signaling by protease-activated receptor 2. (Pubmed Central) - Sep 4, 2021
We also estimated potential gingipain cleavage sites in PAR2 and exposed tethered ligands, which are required for PAR2 internalization and membrane ruffling. The identified mechanism in this study might contribute to the retrogression of sporadic AD in patients after infection with P. gingivalis.
- | Journal: Unrevealing the Proteolytic Activity of RgpB Gingipain from Computational Simulations. (Pubmed Central) - Sep 3, 2021
The mechanism exhibits an unusual role of H211 residue compared with other cysteine proteases but a crucial role of the peptide in triggering the catalysis. Notably, the atomic and energetic particularities found represent a significant contribution to the comprehension of the reaction mechanism and a great opportunity for the design of efficient inhibitors of gingipain RgpB.
- | Journal: Platelet Rich Plasma Inhibits Osteoblast Apoptosis and Actin Cytoskeleton Disruption Induced by Gingipains through Upregulating Integrin β1. (Pubmed Central) - Aug 12, 2021
Platelet rich plasma failed to reduce cell apoptosis and reorganize cytoskeleton after knockdown of integrin β1. In conclusion, platelet rich plasma inhibits gingipain-induced osteoblast apoptosis and actin cytoskeleton disruption by upregulating integrin β1 expression.
- atuzaginstat (COR388) / Cortexyme
[VIRTUAL] An update and baseline Data from the Phase 2/3 GAIN trial of COR388 (atuzaginstat) a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease () - Aug 2, 2021 - Abstract #AAIC2021AAIC_1851;
Subjects enrolled exhibit baseline characteristics consistent with AD and with Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat in mild-moderate AD. The high correlations of AD, periodontal disease, and Pg infections observed in GAIN replicates findings by others and supports a causal role of Pg in AD.
- atuzaginstat (COR388) / Cortexyme
An update and baseline Data from the Phase 2/3 GAIN trial of COR388 (atuzaginstat) a novel bacterial virulence factor inhibitor for the treatment of Alzheimer’s Disease (Convention Ctr - Exhibit Hall F) - Aug 2, 2021 - Abstract #AAIC2021AAIC_1834;
Subjects enrolled exhibit baseline characteristics consistent with AD and with Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat in mild-moderate AD. The high correlations of AD, periodontal disease, and Pg infections observed in GAIN replicates findings by others and supports a causal role of Pg in AD.
- atuzaginstat (COR388) / Cortexyme
[VIRTUAL] An Update and Baseline Data from the Phase 2/3 Gain Trial of COR388 (atuzaginstat) a Novel Bacterial Virulence Factor Inhibitor for the Treatment of Alzheimer’s Disease () - Apr 13, 2021 - Abstract #ASCP2021ASCP_13;
An interim analysis in December 2020 indicated that the study should continue as planned without sample size adjustment. Subjects enrolled exhibit baseline characteristics consistent with AD and with Pg infection, indicating an appropriate population to test the efficacy and safety of atuzaginstat in mild-moderate AD.
- | Journal: Quercetin inhibits virulence properties of Porphyromas gingivalis in periodontal disease. (Pubmed Central) - Feb 27, 2021
Expression of the genes tested was down-regulated in the presence of quercetin. In conclusion, our study demonstrated that quercetin inhibited various virulence factors of P. gingivalis.
- | atuzaginstat (COR388) / Cortexyme
Journal: Porphyromonas Gingivalis and Alzheimer's Disease: Recent findings and potential therapies. (Pubmed Central) - Nov 18, 2020
Oral administration of gingipain inhibitors to mice with established brain infections decreases the abundance of P. gingivalis DNA in brain and mitigates the neurotoxic effects of P. gingivalis infection. Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and Alzheimer's disease.
- | atuzaginstat (COR388) / Cortexyme
Journal: Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388. (Pubmed Central) - Oct 27, 2020
In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans.
- [VIRTUAL] PD-L1 is induced by the periodontal pathogen Porphyromonas gingivalis and can be blocked by small molecule gingipain inhibitors, including atuzaginstat () - Oct 14, 2020 - Abstract #SITC2020SITC_1699;
Further studies to elucidate induction mechanisms are in progress. In esophageal cancer and other cancers infected with Pg, combining gingipain inhibitors with anti-PD-1 therapy may improve treatment outcomes.
- [VIRTUAL] PD-L1 is induced by the periodontal pathogen Porphyromonas gingivalis and can be blocked by small molecule gingipain inhibitors, including atuzaginstat () - Oct 14, 2020 - Abstract #SITC2020SITC_964;
Further studies to elucidate induction mechanisms are in progress. In esophageal cancer and other cancers infected with Pg, combining gingipain inhibitors with anti-PD-1 therapy may improve treatment outcomes.
- atuzaginstat (COR388) / Cortexyme
[VIRTUAL] PHASE 2/3 GAIN TRIAL OF COR388 (ATUZAGINSTAT), A NOVEL BACTERIAL VIRULENCE FACTOR INHIBITOR FOR THE TREATMENT OF ALZHEIMER’S DISEASE: UPDATE AND BASELINE DATA () - Aug 7, 2020 - Abstract #CTAD2020CTAD_59;
In esophageal cancer and other cancers infected with Pg, combining gingipain inhibitors with anti-PD-1 therapy may improve treatment outcomes. Enrollment of the GAIN trial is proceeding according to planned timelines and patients enrolled to date exhibit baseline characteristics consistent with enrollment of appropriate patients that are likely to be responders to COR388 (atuzaginstat).
- atuzaginstat (COR388) / Cortexyme
[VIRTUAL] COR388, a novel gingipain inhibitor, decreases fragmentation of ApoE in the central nervous system of Alzheimers disease patients () - Aug 2, 2020 - Abstract #AAIC2020AAIC_3363;
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 through the generation of fragments. COR388, a small-molecule inhibitor of lysine-gingipain, is currently being tested in a large Phase 2/3 clinical study in subjects with mild-to-moderate AD.
- atuzaginstat (COR388) / Cortexyme
[VIRTUAL] Comprehensive Alzheimers pathology is induced by P. gingivalis infection: COR388 and other gingipain inhibitors protect against synaptic loss () - Aug 2, 2020 - Abstract #AAIC2020AAIC_2185;
We demonstrate in an in vitro model system that P. gingivalis infection can result in a neurodegenerative phenotype consistent with pathology found in Alzheimers disease. With this model we show that exposure of neurons to P. gingivalis infection results in synaptic loss and dystrophic neurites which can be prevented by gingipain inhibitors.
- atuzaginstat (COR388) / Cortexyme
[VIRTUAL] Targeting Porphyromonas gingivalis to treat Alzheimers disease and comorbid cardiovascular disease () - Aug 2, 2020 - Abstract #AAIC2020AAIC_516;
COR388, a novel lysine-gingipain inhibitor, is currently being tested in a Phase 2/3 clinical trial to target Pg for the treatment of AD. Based on the current preclinical data reported here, COR388 has the potential to attenuate atheroma formation and systemic inflammation in Pg- induced atherosclerosis and therefore may have beneficial effects on comorbid cardiovascular disease in Pg-associated AD.