Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock

Kim, Ye-Ram; Koh, Hyun Jung; Kim, Jae-Sung; Yun, Jin-Seung; Jang, Kiseok; Lee, Joo‐Youn; Jung, Jae U.; Yang, Chul–Su

doi:10.1016/j.biomaterials.2016.05.046

Cited by 22 publications

(37 citation statements)

References 54 publications

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“…PKCα-phosphorylated GRA8 associates with mitochondrial SIRT3; SIRT3 associates with ATP5A1 and controls its activity by affecting acetylation status [8,9]. Deacetylated ATP5A1 participates in several mitochondrial functions, and SIRT3 can orchestrate the overall changes in mitochondrial function, that are critical for cancer growth [14,22]. We determined whether rGRA8 or its mutants caused cell death by MTT assay in various cancer cell lines.…”

Section: Rgra8-induces Colon Cell Death Via Pkcα-sirt3-atp5a1 Pathwaysmentioning

confidence: 99%

“…Our earlier work on interaction of GRA8 revealed that the 40-amino acid sequence (aa 183-222) or 28-amino acid sequence (aa 242-269) at the C-terminus of GRA8 is sufficient for mitochondrial targeting or ATP5A1/SIRT3 interaction, respectively [8]. Thus, the transduction-domain www.oncotarget.com of HIV-1 Tat protein was added to the 9-10-amino acid sequence of GRA8 as a retro-inverso peptide, known as the Tat-GRA8 peptide, for intracellular delivery to prevent proteolytic breakdown [22,23] (Tables 1 and 2). These peptides were tested for their potential minimal residues of GRA8 for mitochondrial targeting and ATP5A1/SIRT3 interaction in 293T cells.…”

Section: Atram-conjugated Gra8 Peptide Designed To Target Tumorsmentioning

confidence: 99%

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Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

et al. 2020

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Targeted tumor and efficient, specific biological drug delivery in vivo has been one of the main challenges in protein-based cancer-targeted therapies. Mitochondria are potential therapeutic targets for various anti-cancer drugs. We have previously reported that protein kinase Cα-mediated phosphorylation of Toxoplasma gondii GRA8 is required for mitochondrial trafficking and regulating the interaction of the C-terminal of GRA8 with ATP5A1/SIRT3 in mitochondria. Furthermore, SIRT3 facilitates ATP5A1 deacetylation, mitochondrial activation, and subsequent antiseptic activity in vivo. Herein we developed a recombinant acidity-triggered rational membrane (ATRAM)-conjugated multifunctional GRA8 peptide (rATRAM-G8-M/AS) comprising ATRAM as the cancer-targeting cell-penetrating peptide, and essential/ minimal residues for mitochondrial targeting or ATP5A1/SIRT3 binding. This peptide construct showed considerably improved potency about cancer cell death via mitochondria activity and biogenesis compared with rGRA8 alone in HCT116 human carcinoma cells, reaching an IC 50 value of up to 200-fold lower in vitro and 500-fold lower in vivo. Notably, rATRAM-G8-M/AS treatment showed significant therapeutic effects in a mouse xenograft model through mitochondrial metabolic resuscitation, and it produced negligible immunogenicity and immune responses in vivo. Thus, these results demonstrate that rATRAM-G8-M/AS represents a useful therapeutic strategy against tumors, particularly colon cancer. This strategy represents an urgently needed paradigm shift for therapeutic intervention.

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Section: Rgra8-induces Colon Cell Death Via Pkcα-sirt3-atp5a1 Pathwaysmentioning

confidence: 99%

Section: Atram-conjugated Gra8 Peptide Designed To Target Tumorsmentioning

confidence: 99%

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

et al. 2020

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“…Raw264.7 stable cell lines were generated using a standard selection protocol with 2 μg/ml of puromycin. Mouse primary bone marrow derived-macrophages (BMDMs) were isolated from C57BL/6 mice and cultured in DMEM for 3-5 days in the presence of 25 ng/ml recombinant macrophage colony stimulating factor (R&D Systems, 416-ML, Minneapolis, MN, USA), as described previously 23 . Human adherent monocytes were prepared from PBMCs donated by healthy subjects, as described previously 19 .…”

Section: Cellsmentioning

confidence: 99%

“…The entire mixture Protein purification and mass spectrometry. To identify p22phox-binding proteins, precipitates were washed extensively with lysis buffer 23 . Proteins bound to beads were eluted and separated on a NuPAGE 4-12% Bis-Tris gradient gel (Life Technologies).…”

Section: Cellsmentioning

confidence: 99%

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Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis

Kim

et al. 2020

Sci Rep

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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC 50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA. Rheumatoid arthritis (RA) presents with characteristic chronic synovial hyperplasia and inflammation, and is a type of systemic autoimmune disease. Besides, in RA is also associated with invasion of inflammation and hyperplasia into the adjacent bone and cartilage, which cause slow degeneration of the knee joints 1. The current drugs for treating RA, such as disease-modifying anti-rheumatic drugs (methotrexate), nonsteroidal anti-inflammatory drugs (NSAID), steroids (prednisone), glucocorticoids, immunosuppressants, and biological therapies (TNF-α and IL-1 activity blocking monoclonal antibodies), have dramatically improved prognosis 2,3. Nevertheless, about 20-40% proportion of patients fail to respond to current therapies, and biological therapies raises the risk of serious infection 1,4,5. Therefore, attention has urgently focused on alternative RA therapeutics with high efficacy and reduced side effects.

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ROS Scavenging Biopolymers for Anti‐Inflammatory Diseases: Classification and Formulation

Zhang

Yang

et al. 2020

Adv Materials Inter

115

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Reactive oxygen species (ROS), the byproducts of aerobic metabolism, is a class of crucial molecules in physiological processes, nevertheless, would induce a series of inflammatory responses when overexpression. Excessive or inappropriate inflammation contributes to a range of acute and chronic human inflammatory diseases. In recent years, ROS scavenging agents have been widely regarded as a kind of potential therapeutic substances due to their abilities of delaying and/or inhibiting the oxidative stress in physiological microenvironments. ROS scavenging biopolymers are a group of agents that commonly have strong ROS scavenging ability and pharmacokinetic potential compared to similar low molecular weight agents. In this review, the generation and clearance of ROS in physiological processes, as well as the effects of ROS inflammatory diseases are introduced. Furthermore, the classification, macromolecular structure, and scavenging mechanism of those antioxidant polymers are systematically described and discussed, which aim to provide a guiding theoretical reference of designing effectively ROS scavenging biopolymers for anti‐inflammatory disease therapy.

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Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock

Cited by 22 publications

References 54 publications

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

Toxoplasma gondii GRA8-derived peptide immunotherapy improves tumor targeting of colorectal cancer

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis

ROS Scavenging Biopolymers for Anti‐Inflammatory Diseases: Classification and Formulation

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