RESUMO
Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a ß-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.
Assuntos
Alcenos , Inflamação , Proteínas de Membrana , Nitrocompostos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Animais , Inflamação/tratamento farmacológico , Humanos , Camundongos , Alcenos/química , Alcenos/farmacologia , Nitrocompostos/química , Nitrocompostos/farmacologia , Relação Estrutura-AtividadeRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Antiviral 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.
Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fumarato de Dimetilo/agonistas , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Succinatos/agonistas , Adulto , Antioxidantes/farmacologia , Betacoronavirus/metabolismo , COVID-19 , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I , Pulmão/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Succinatos/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi-Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.
Assuntos
Ácidos Graxos/metabolismo , Herpes Simples/metabolismo , Herpesvirus Humano 2/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Doenças Autoimunes do Sistema Nervoso/patologia , Herpes Simples/genética , Herpes Simples/patologia , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Lipoilação , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/patologia , Células RAW 264.7RESUMO
The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases.