Common Pharmacophore of Structurally Distinct Small-Molecule Inhibitors of Intracellular Retrograde Trafficking of Ribosome Inactivating Proteins

Shen, Yu; Park, Jewn Giew; Kahn, Jennifer Nielsen; Tumer, Nilgun E.; Pang, Yuan Ping

doi:10.1038/srep03397

Cited by 8 publications

(5 citation statements)

References 27 publications

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“…Moreover, our findings further demonstrate the potential of Retro-2.1 to be developed as a promising broad-spectrum drug against toxins, viruses and other pathogens [19,49]. As a number of derivatives of Retro-2 c y c l and Retro-2.1 have been synthesized, these analogs are potential lead compounds that would contribute considerably to anti-HSV-2 drug development [13,24,[50][51][52].…”

Section: Discussionsupporting

confidence: 60%

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Dai

et al. 2018

Journal of Microbiology and Biotechnology

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could inhibit HSV-2 infection, with 50% inhibitory concentrations of 5.58 µM and 6.35 µM in cytopathic effect inhibition and plaque reduction assays, respectively. The cytotoxicity of Retro-2.1 was relatively low, with a 50% cytotoxicity concentration of 116.5 µM.We also preliminarily identified that Retro-2.1 exerted the antiviral effect against HSV-2 by a dual mechanism of action on virus entry and late stages of infection. Therefore, our study for the first time demonstrated Retro-2.1 as an effective antiviral agent against HSV-2 in vitro with targets distinct from those of nucleoside analogs.Keywords: Herpes simplex virus type 2, Retro-2.1, antiviral effect, entry, late stage, vesicle transport 850 Dai et al. J. Microbiol. Biotechnol.

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Section: Discussionsupporting

confidence: 60%

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Dai

et al. 2018

Journal of Microbiology and Biotechnology

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“…In the next series of experiments, we assessed the requirement for CdtB localization using the inhibitor, Retro-2, a nontoxic inhibitor of endosome-to-Golgi retrograde transport. This inhibitor has been employed in other studies to protect cells from toxins, such as ricin, cholera, and Shiga (35,36); it also inhibits infection by viruses, such as polyoma, papilloma, AAV, and filoviruses by inhibiting retrograde transport (37-40). Retro-2 has been reported to not alter compartment morphology, endogenous retrograde cargos, or other trafficking steps, such as endocytosis, recycling and degradation (40).…”

Section: Resultsmentioning

confidence: 99%

Internalization and Intoxication of Human Macrophages by the Active Subunit of the Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Is Dependent Upon Cellugyrin (Synaptogyrin-2)

et al. 2020

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The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is a heterotrimeric AB 2 toxin capable of inducing cell cycle arrest and apoptosis in lymphocytes and other cell types. Recently, we have demonstrated that human macrophages are resistant to Cdt-induced apoptosis but are susceptible to toxininduced pro-inflammatory cytokine response involving activation of the NLRP3 inflammasome. Exposure to Cdt results in binding to the cell surface followed by internalization and translocation of the active subunit, CdtB, to intracellular compartments. Internalization involves hijacking of retrograde pathways; treatment of cells with Retro-2 leads to a decrease in CdtB-Golgi association. These events are dependent upon toxin binding to cholesterol in the context of lipid rich membrane microdomains often referred to as lipid rafts. We now demonstrate that within 1 h of exposure of macrophages to Cdt, CdtB is internalized and found primarily within lipid rafts; concurrently, cellugyrin (synaptogyrin-2) also translocates into lipid rafts. Further analysis by immunoprecipitation indicates that CdtB associates with complexes containing both cellugyrin and Derlin-2. Moreover, a human macrophage cell line deficient in cellugyrin expression (THP-1 Cg−) challenged with Cdt failed to internalize CdtB and was resistant to the Cdt-induced pro-inflammatory response. We propose that lipid rafts along with cellugyrin play a critical role in the internalization and translocation of CdtB to critical intracellular target sites in human macrophages. These studies provide the first evidence that cellugyrin is expressed in human macrophages and plays a critical role in Cdt toxicity of these cells.

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“…Indeed, although DAPG and GI294023X co-treatment increased intracellular Aβ levels, DAPG alone did not provoke a decrease in intracellular Aβ levels but rather an increase in 293sw cells or no change in the primary astrocytes, indicating that ADAM10 only partly participated in the response to DAPG and further mechanisms affected Aβ secretion. Therefore, we modulated the intracellular trafficking leading to protein secretion using various inhibitors, i.e., GCA and BFA [ 33 ], CI-976 [ 34 ], ZCL-278 [ 35 ], vacuolin-1 [ 36 ], EHNA [ 37 ], and retro-2 [ 38 ]. ZCL-278, an inhibitor of CDC42 mainly located in the Golgi complex, blocked the most effectively DAPG-mediated changes of sAPPα levels in 293sw cells and had similar effect than those of the ADAM10 inhibitor ( Figure S4 ).…”

Section: Discussionmentioning

confidence: 99%

2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease

Jang

Choi

Kim

et al. 2022

Cells

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There is currently no effective treatment against Alzheimer’s disease (AD), although many strategies have been applied to reduce beta-amyloid (Aβ) levels. Here, we investigated 2,4-diacetylphloroglucinol (DAPG) effects on Aβ levels and mechanisms of action. DAPG was the most effective phloroglucinol derivative for reducing Aβ levels, without being toxic, in various models including HEK293 cells overexpressing Swedish mutant amyloid precursor protein (APP) (293sw), primary astrocytes isolated from APPsw/PS1dE9 transgenic mice, and after intrahippocampal injection of DAPG in APPsw/PS1dE9 transgenic mice. DAPG-mediated Aβ reduction was associated with increased soluble APPα (sAPPα) levels mediated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) but not ADAM17. ADAM10 inhibition in DAPG-treated cells prevented the effects on sAPPα but only partly on intracellular and secreted Aβ. To identify regulators of sAPPα and Aβ secretion, various inhibitors of intracellular trafficking were administered with DAPG. Brefeldin A (BFA) reversed DAPG-mediated changes in Aβ secretion in 293sw cells, whereas golgicide A (GCA) and BFA were effective in primary astrocytes, indicating a cell type-specific regulation of the trafficking. Moreover, GCA or BFA effects on sAPPα, but not Aβ, levels in primary astrocytes resembled those of ADAM10 inhibition, indicating at least partly independent trafficking pathways for sAPPα and Aβ. In conclusion, DAPG might be a promising drug candidate against AD regulating ADAM10 and intracellular trafficking, but optimizing DAPG ability to cross the BBB will be needed.

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Common Pharmacophore of Structurally Distinct Small-Molecule Inhibitors of Intracellular Retrograde Trafficking of Ribosome Inactivating Proteins

Cited by 8 publications

References 27 publications

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Internalization and Intoxication of Human Macrophages by the Active Subunit of the Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Is Dependent Upon Cellugyrin (Synaptogyrin-2)

2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer’s Disease

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