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.

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 anti-oxidant 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 potent cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit 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, induction of NRF2 by 4-OI and DMF limited 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 suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence Summary: NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

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Seasonal prey bursts are important for the life cycles and energy budgets of many predators. This study documents the diet and, especially, the importance of the ephemeral occurrence of capelin as prey for Atlantic cod (Gadus morhua) in Godthaabsfjord, west Greenland, over an annual cycle. The cod showed clear differences in diet composition on the 11 sampling dates resulting in a spring-summer, late summer-autumn and winter cluster. Moreover, a single sampling date, 12 May, was defined by cod gorge feeding on spawning capelin, which led to average stomach contents 4.3 times higher than the average for the remaining sampling dates. Changes in nitrogen stable isotope values from 22 April to 7 July in cod liver and muscle tissue were used to calculate the consumption of capelin. Based on this, the consumption of capelin varied between 538 and 658 g wet weight for a 1.3 kg cod. Using published consumption/biomass estimates and observed growth rates, the capelin intake corresponds to 10.1%-33.3% of the annual food consumption and accounts for 28.1%-34.5% of the annual growth of the cod. The present study documents the omnivorous feeding mode of Atlantic cod but highlights the utilization and importance of ephemeral prey bursts for the annual energy budget of the cod. It is hypothesized that access to capelin is critical for the postspawning recovery of Godthaabsfjord cod.

The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (−)‐vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity. The synthesis allows for a high degree of flexibility in modifying the macrocyclic framework, including the formation of all possible stereoisomers. In total, 18 analogues were prepared. Two analogues with minor structural modifications showed clearly enhanced cancer cell line selectivity and reduced toxicity. Moreover, these compounds possessed broad inhibitory activity against innate immunological pathways in human PBMCs, including the DNA‐sensing cGAS‐STING pathway. Initial mechanistic characterization suggests a surprising impairment of the STING‐TBK1 interaction.