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Article: Anti-Influenza Drug Discovery and Development: Targeting the Virus and Its Host by All Possible Means.

Terrier, Olivier / Slama-Schwok, Anny

Advances in experimental medicine and biology

2021 Volume 1322, Page(s) 195–218

Abstract: Infections by influenza virus constitute a major and recurrent threat for human health. Together with vaccines, antiviral drugs play a key role in the prevention and treatment of influenza virus infection and disease. Today, the number of antiviral ... ...

Abstract	Infections by influenza virus constitute a major and recurrent threat for human health. Together with vaccines, antiviral drugs play a key role in the prevention and treatment of influenza virus infection and disease. Today, the number of antiviral molecules approved for the treatment of influenza is relatively limited, and their use is threatened by the emergence of viral strains with resistance mutations. There is therefore a real need to expand the prophylactic and therapeutic arsenal. This chapter summarizes the state of the art in drug discovery and development for the treatment of influenza virus infections, with a focus on both virus-targeting and host cell-targeting strategies. Novel antiviral strategies targeting other viral proteins or targeting the host cell, some of which are based on drug repurposing, may be used in combination to strengthen our therapeutic arsenal against this major pathogen.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Drug Discovery ; Humans ; Influenza, Human/drug therapy ; Orthomyxoviridae ; Orthomyxoviridae Infections ; Virus Replication
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2021-07-13
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-981-16-0267-2_8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor

Dilly, Sébastien / Romero, Miguel / Solier, Stéphanie / Feron, Olivier / Dessy, Chantal / Slama Schwok, Anny

Antioxidants. 2023 Feb. 10, v. 12, no. 2

2023

Abstract: ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer ... ...

Abstract	ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal cell functions is a new therapeutic avenue. In this paper, we describe new inhibitors of NADPH oxidase (NOX), a key enzyme in many cells of the tumor microenvironment. The first inhibitor, called Nanoshutter-1, NS1, decreased the level of tumor-promoting “M2” macrophages differentiated from human blood monocytes. NS1 disrupted the active NADPH oxidase-2 (NOX2) complex at the membrane and in the mitochondria of the macrophages, as shown by confocal microscopy. As one of the characteristics of tumor invasion is hypoxia, we tested whether NS1 would affect vascular reactivity by reducing ROS or NO levels in wire and pressure myograph experiments on isolated blood vessels. The results show that NS1 vasodilated blood vessels and would likely reduce hypoxia. Finally, as both NOX2 and NOX4 are key proteins in tumors and their microenvironment, we investigated whether NS1 would probe these proteins differently. Models of NOX2 and NOX4 were generated by homology modeling, showing structural differences at their C-terminal NADPH site, in particular in their last Phe. Thus, the NADPH site presents an unexploited chemical space for addressing ligand specificity, which we exploited to design a novel NOX2-specific inhibitor targeting variable NOX2 residues. With the proper smart vehicle to target specific cells of the microenvironment as TAMs, NOX2-specific inhibitors could open the way to new precision therapies.
Keywords	NAD(P)H oxidase (H2O2-forming) ; cell death ; confocal microscopy ; humans ; hypoxia ; immunotherapy ; ligands ; macrophages ; mitochondria ; monocytes ; neoplasms
Language	English
Dates of publication	2023-0210
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12020440
Database	NAL-Catalogue (AGRICOLA)

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Article: Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor.

Dilly, Sébastien / Romero, Miguel / Solier, Stéphanie / Feron, Olivier / Dessy, Chantal / Slama Schwok, Anny

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 2

Abstract	ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal cell functions is a new therapeutic avenue. In this paper, we describe new inhibitors of NADPH oxidase (NOX), a key enzyme in many cells of the tumor microenvironment. The first inhibitor, called Nanoshutter-1, NS1, decreased the level of tumor-promoting "M2" macrophages differentiated from human blood monocytes. NS1 disrupted the active NADPH oxidase-2 (NOX2) complex at the membrane and in the mitochondria of the macrophages, as shown by confocal microscopy. As one of the characteristics of tumor invasion is hypoxia, we tested whether NS1 would affect vascular reactivity by reducing ROS or NO levels in wire and pressure myograph experiments on isolated blood vessels. The results show that NS1 vasodilated blood vessels and would likely reduce hypoxia. Finally, as both NOX2 and NOX4 are key proteins in tumors and their microenvironment, we investigated whether NS1 would probe these proteins differently. Models of NOX2 and NOX4 were generated by homology modeling, showing structural differences at their C-terminal NADPH site, in particular in their last Phe. Thus, the NADPH site presents an unexploited chemical space for addressing ligand specificity, which we exploited to design a novel NOX2-specific inhibitor targeting variable NOX2 residues. With the proper smart vehicle to target specific cells of the microenvironment as TAMs, NOX2-specific inhibitors could open the way to new precision therapies.
Language	English
Publishing date	2023-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12020440
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Article ; Online: Neuropeptides, New Ligands of SARS-CoV-2 Nucleoprotein, a Potential Link between Replication, Inflammation and Neurotransmission.

Henri, Julien / Minder, Laetitia / Mohanasundaram, Kevin / Dilly, Sébastien / Goupil-Lamy, Anne / Di Primo, Carmelo / Slama Schwok, Anny

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 22

Abstract: This work identifies new ligands of the nucleoprotein N of SARS-CoV-2 by in silico screening, which used a new model of N, built from an Alphafold model refined by molecular dynamic simulations. The ligands were neuropeptides, such as substance P (1-7) ... ...

Abstract	This work identifies new ligands of the nucleoprotein N of SARS-CoV-2 by in silico screening, which used a new model of N, built from an Alphafold model refined by molecular dynamic simulations. The ligands were neuropeptides, such as substance P (1-7) and enkephalin, bound at a large site of the C-terminal or associated with the N-terminal β-sheet. The BA4 and BA5 Omicron variants of N also exhibited a large site as in wt N, and an increased flexibility of the BA5 variant, enabling substance P binding. The binding sites of some ligands deduced from modeling in wt N were assessed by mutation studies in surface plasmon resonance experiments. Dynamic light scattering showed that the ligands impeded RNA binding to N, which likely inhibited replication. We suggest that the physiological role of these neuropeptides in neurotransmission, pain and vasodilation for cholecystokinin and substance P could be altered by binding to N. We speculate that N may link between viral replication and multiple pathways leading to long COVID-19 symptoms. Therefore, N may constitute a "danger hub" that needs to be inhibited, even at high cost for the host. Antivirals targeted to N may therefore reduce the risk of brain fog and stroke, and improve patients' health.
MeSH term(s)	Humans ; Nucleoproteins ; SARS-CoV-2 ; COVID-19 ; Ligands ; Substance P ; Neuropeptides ; Synaptic Transmission ; Inflammation
Chemical Substances	Nucleoproteins ; Ligands ; Substance P (33507-63-0) ; Neuropeptides
Language	English
Publishing date	2022-11-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27228094
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Article: Design of Light-Sensitive Triggers for Endothelial NO-Synthase Activation.

Dilly, Sébastien / Roman, Linda J / Bogliotti, Nicolas / Xie, Juan / Deprez, Eric / Slama-Schwok, Anny

Antioxidants (Basel, Switzerland)

2020 Volume 9, Issue 2

Abstract: ...

Abstract	:
Language	English
Publishing date	2020-01-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox9020089
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Article ; Online: Mechanism of melanoma cells selective apoptosis induced by a photoactive NADPH analogue.

Rouaud, Florian / Boucher, Jean-Luc / Slama-Schwok, Anny / Rocchi, Stéphane

Oncotarget

2016 Volume 7, Issue 50, Page(s) 82804–82819

Abstract: Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional ... ...

Abstract	Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment.NS1 established an early Endoplasmic Reticulum stress by the early release of calcium mediated by (a) calcium-dependent redox-sensitive ion channel(s). These events initiated autophagy and apoptosis in all tested melanoma cells independently of their mutational status. The autophagy promoted by NS1 was incomplete. The autophagic flux was blocked at late stage events, consistent with the accumulation of p62, and a close localization of LC3 with NS1 associated with NS1 inhibition of NOX1 in autophagosomes. This hypothesis of a specific incomplete autophagy and apoptosis driven by NS1 was comforted by the use of siRNAs and pharmacological inhibitors blocking different processes. This study highlights the potential therapeutic interest of NS1 inducing cell death by triggering a selective ER stress and incomplete autophagy in melanoma cells harbouring wt and BRAF mutation.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Autophagy/drug effects ; Calcium/metabolism ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Inhibitors/pharmacology ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Microtubule-Associated Proteins/metabolism ; Mutation ; NADP/analogs & derivatives ; NADP/pharmacology ; NADPH Oxidases/antagonists & inhibitors ; NADPH Oxidases/metabolism ; Proto-Oncogene Proteins B-raf/metabolism ; RAW 264.7 Cells ; RNA Interference ; Reactive Oxygen Species/metabolism ; Sequestosome-1 Protein/metabolism ; Signal Transduction/drug effects ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Time Factors ; Transfection
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Reactive Oxygen Species ; SQSTM1 protein, human ; Sequestosome-1 Protein ; NADP (53-59-8) ; NADPH Oxidases (EC 1.6.3.-) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2016-09-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.12651
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Article ; Online: Identification of a Novel Complex between the Nucleoprotein and PA(1-27) of Influenza A Virus Polymerase.

Vidic, Jasmina / Noiray, Magali / Bagchi, Angshuman / Slama-Schwok, Anny

Biochemistry

2016 Volume 55, Issue 31, Page(s) 4259–4262

Abstract: The structure of the ribonucleoprotein complexes is crucial to viral transcription and replication of influenza virus, but association of the nucleoprotein (NP) with the polymerase remains to be characterized at the molecular level. Here, we identify a ... ...

Abstract	The structure of the ribonucleoprotein complexes is crucial to viral transcription and replication of influenza virus, but association of the nucleoprotein (NP) with the polymerase remains to be characterized at the molecular level. Here, we identify a peptide of the polymerase acidic subunit PA(1-27) that associates with NP. Docking and molecular dynamics simulations suggest a similar NP binding site with PA(1-27) and PA(1-186). The PA(1-27)-NP complex is characterized by surface plasmon resonance and fluorescence using recombinant NP proteins and by pull-down assays in infected cells. The PA(1-27)-NP complex may have a role in the final steps of transcription and replication.
MeSH term(s)	Animals ; Dogs ; Influenza A Virus, H1N1 Subtype/chemistry ; Influenza A Virus, H1N1 Subtype/physiology ; Madin Darby Canine Kidney Cells ; Models, Molecular ; Molecular Dynamics Simulation ; Multiprotein Complexes/chemistry ; Protein Interaction Domains and Motifs ; Protein Subunits/chemistry ; RNA Replicase/chemistry ; RNA-Binding Proteins/chemistry ; Recombinant Proteins/chemistry ; Spectrometry, Fluorescence ; Surface Plasmon Resonance ; Viral Core Proteins/chemistry ; Viral Proteins/chemistry
Chemical Substances	Multiprotein Complexes ; NP protein, Influenza A virus ; PA protein, influenza viruses ; Protein Subunits ; RNA-Binding Proteins ; Recombinant Proteins ; Viral Core Proteins ; Viral Proteins ; RNA Replicase (EC 2.7.7.48)
Language	English
Publishing date	2016-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.6b00514
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 217: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Protein disulfide isomerase may facilitate the efflux of nitrite derived S-nitrosothiols from red blood cells.

Kallakunta, Vasantha Madhuri / Slama-Schwok, Anny / Mutus, Bulent

Redox biology

2013 Volume 1, Page(s) 373–380

Abstract: Protein disulfide isomerase (PDI) is an abundant protein primarily found in the endoplasmic reticulum and also secreted into the blood by a variety of vascular cells. The evidence obtained here, suggests that PDI could directly participate in the efflux ... ...

Abstract	Protein disulfide isomerase (PDI) is an abundant protein primarily found in the endoplasmic reticulum and also secreted into the blood by a variety of vascular cells. The evidence obtained here, suggests that PDI could directly participate in the efflux of NO(+) from red blood cells (RBC). PDI was detected both in RBC membranes and in the cytosol. PDI was S-nitrosylated when RBCs were exposed to nitrite under ∼50% oxygen saturation but not under ∼100% oxygen saturation. Furthermore, it was observed that hemoglobin (Hb) could promote PDI S-nitrosylation in the presence of ∼600 nM nitrite. In addition, three lines of evidence were obtained for PDI-Hb interactions: (1) Hb co-immunoprecipitated with PDI; (2) Hb quenched the intrinsic PDI fluorescence in a saturable manner; and (3) Hb-Fe(II)-NO absorption spectrum decreased in a [PDI]-dependent manner. Finally, PDI was detected on the surface RBC under ∼100% oxygen saturation and released as soluble under ∼50% oxygen saturation. The soluble PDI detected under ∼50% oxygen saturation was S-nitrosylated. Based on these data it is proposed that PDI is taken up by RBC and forms a complex with Hb. Hb-Fe(II)-NO that is formed from nitrite reduction under ∼50% O2, then transfers NO(+) to either Hb-Cys β93 or directly to PDI resulting in S-nitroso-PDI which transverses the RBC membrane and attaches to the RBC surface. When RBCs enter tissues the S-nitroso-PDI is released from the RBC-surface into the blood where its NO(+) is transferred into the endothelium thereby inducing vasodilation, suggesting local oxygen-dependent dynamic interplays between nitrite, NO and S-nitrosylation.
MeSH term(s)	Cells, Cultured ; Erythrocytes/enzymology ; Erythrocytes/metabolism ; Hemoglobins/metabolism ; Humans ; Nitric Oxide/metabolism ; Nitrites/metabolism ; Oxygen/metabolism ; Protein Disulfide-Isomerases/metabolism ; S-Nitrosothiols/metabolism
Chemical Substances	Hemoglobins ; Nitrites ; S-Nitrosothiols ; Nitric Oxide (31C4KY9ESH) ; Protein Disulfide-Isomerases (EC 5.3.4.1) ; Oxygen (S88TT14065)
Language	English
Publishing date	2013-07-16
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2013.07.002
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Article ; Online: Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues.

International journal of molecular sciences

2023 Volume 24, Issue 4

Abstract: Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we ... ...

Abstract	Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47
MeSH term(s)	Humans ; Animals ; Mice ; Macrophage Colony-Stimulating Factor/metabolism ; Caspase 7/metabolism ; Caspases/metabolism ; Reactive Oxygen Species/metabolism ; Macrophages/metabolism ; NADPH Oxidases/metabolism ; Monocytes/metabolism
Chemical Substances	Macrophage Colony-Stimulating Factor (81627-83-0) ; Caspase 7 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-) ; Reactive Oxygen Species ; NADPH Oxidases (EC 1.6.3.-)
Language	English
Publishing date	2023-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24044151
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Article: Identification of a Novel Complex between the Nucleoprotein and PA(1â27) of Influenza A Virus Polymerase

Vidic, Jasmina / Noiray Magali / Bagchi Angshuman / Slama-Schwok Anny

Biochemistry. 2016 Aug. 09, v. 55, no. 31

2016

Abstract	The structure of the ribonucleoprotein complexes is crucial to viral transcription and replication of influenza virus, but association of the nucleoprotein (NP) with the polymerase remains to be characterized at the molecular level. Here, we identify a peptide of the polymerase acidic subunit PA(1â27) that associates with NP. Docking and molecular dynamics simulations suggest a similar NP binding site with PA(1â27) and PA(1â186). The PA(1â27)âNP complex is characterized by surface plasmon resonance and fluorescence using recombinant NP proteins and by pull-down assays in infected cells. The PA(1â27)âNP complex may have a role in the final steps of transcription and replication.
Keywords	Influenza A virus ; binding sites ; fluorescence ; molecular dynamics ; molecular models ; nucleoproteins ; ribonucleoproteins ; surface plasmon resonance
Language	English
Dates of publication	2016-0809
Size	p. 4259-4262.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021%2Facs.biochem.6b00514
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 217: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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