Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.</p

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.</p

Diversity Focused Semisyntheses of Tetronate Polyether Ionophores

The polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many family members possess highly potent antimicrobial activity and a few selected compounds have ability to target particularly aggressive cancer cells. Despite these interesting perspectives, a detailed understanding of the cellular mode-of-action of polyether ionophores is generally lacking. In principle, broad mapping of structure-activity relationships across several biological activities could provide mechanistic insights as well as identification of lead structures but access to structural diversity within the overall class is synthetically very challenging. In this manuscript, we demonstrate that novel polyether ionophores can be constructed by recycling components of highly abundant polyethers. We provide the first examples of synthetically incorporating halogen-functionalized tetronic acids as cation-binding groups into polyether ionophores and we identify analogs with strong anti-bacterial activity and minimal effects on mammalian cells

Stendomycin and Pantomycin Are Identical Natural Products: Preparation of a Functionalized Bioactive Analogue

The natural products pantomycin and stendomycin were both reported as antimicrobial agents. We demonstrate by gene cluster analysis, LC–MS analysis, and isolation that these polypeptides are identical, and we identify previously unknown congeners. We show that stendomycin can be chemically modified at its electrophilic dehydrobutyrine moiety yielding the first bioactive analogue of this natural product which can undergo additional functionalization. This compound may be a valuable starting point for molecular probe development, and we invite its distribution to the scientific community

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity

The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs

Consumer behavior : perilaku konsumen dan strategi pemasaran jilid 2

+hlm.;c

Author Correction: SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

An amendment to this paper has been published and can be accessed via a link at the top of the paper

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Versiones preprint disponibles en: http://hdl.handle.net/10261/216920 y http://hdl.handle.net/10261/217161Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.This research work was supported by Ester M og Konrad Kristian Sigurdssons Dyreværnsfond, Beckett-Fonden, Kong Christian IX og Dronning Louises Jubilæumslegat, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis´ legat, Købmand I Odense Johan og Hanne Weimann Født Seedorffs Legat, Hørslev Fonden, UK Medical Research Council (MRC core funding of the MRC Human Immunology Unit; JR), Lundbeck foundation (R303-2018-3379 and R219-2016-878, and R268-2016-3927), and Independent Research Fund Denmark – Medical Sciences (9039-00078B, 4004-00047B, and 0214-00001B). CarlsbergFoundation (Semper Ardens) and European Research Council (ERC-AdG ENVISION; 786602). Marie Skłodowska-Curie Action of the European Commission # 813343 and Italian Cancer Research Society #22891 to JH.Peer reviewe