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Infectious diseases are a continues threat to human health and the economy worldwide. The latest example is the global pandemic of COVID-19 caused by SARS-CoV-2. Antibody therapy and vaccines are promising approaches to treat the disease; however, they have bottlenecks: they might have low efficacy or narrow breadth due to the continuous emergence of new strains of the virus or antibodies could cause antibody-dependent enhancement (ADE) of infection. To address these bottlenecks, I propose the use of 24-meric ferritin for the synthesis of mosaic nanocages to deliver a cocktail of antibodies or nanobodies alone or in combination with another therapeutic, like a nucleotide analogue, to mimic the viral entry process and deceive the virus, or to develop mosaic vaccines. I argue that available data showing the effectiveness of ferritin-antibody conjugates in targeting specific cells and ferritin-haemagglutinin nanocages in developing influenza vaccines strongly support my proposals.

ISG products are believed to directly block viral replication. We propose an alternative mechanism based on emerging evidence. We discuss that the metabolic products of two ISG proteins, namely RSAD2 and NOS, inhibit activity of GAPDH to regulate central carbon metabolism and support a broad‐spectrum antiviral immune response via at least four mechanisms: eicosanoids storm, antigen cross‐presentation via MHC‐I, modulating NFAT and NF‐κB pathways, and S‐nitrosylation of viral proteins., In response to viral infections, the innate immune system rapidly activates expression of several interferon‐stimulated genes (ISGs), whose protein and metabolic products are believed to directly interfere with the viral life cycle. Here, we argue that biochemical reactions performed by two specific protein products of ISGs modulate central carbon metabolism to support a broad‐spectrum antiviral response. We demonstrate that the metabolites generated by metalloenzymes nitric oxide synthase and the radical S‐adenosylmethionine (SAM) enzyme RSAD2 inhibit the activity of the housekeeping and glycolytic enzyme glyceraldehyde 3‐phosphate dehydrogenase (GAPDH). We discuss that this inhibition is likely to stimulate a range of metabolic and signalling processes to support a broad‐spectrum immune response. Based on these analyses, we propose that inhibiting GAPDH in individuals with deteriorated cellular innate immune response like elderly might help in treating viral diseases such as COVID‐19.

A high-valent Fe(IV) species is proposed to be generated from the decay of a peroxodiferric intermediate in the catalytic cycle at the di-iron cofactor center of dioxygen-activating enzymes such as methane monooxygenase. However, it is believed that this intermediate is not formed in the di-iron substrate site of ferritin, where oxidation of Fe(II) substrate to Fe(III) (the ferroxidase reaction) occurs also via a peroxodiferric intermediate. In opposition to this generally accepted view, here we present evidence for the occurrence of a high-valent Fe(IV) in the ferroxidase reaction of an archaeal ferritin, which is based on trapped intermediates obtained with the freeze-quench technique and combination of spectroscopic characterization. We hypothesize that a Fe(IV) intermediate catalyzes oxidation of excess Fe(II) nearby the ferroxidase center.

The iron-storage protein, ferritin, is widely found in all Domains of life. A conserved diiron center in ferritin catalyzes oxidation of Fe(II) and regulates storage of the resultant Fe(III) oxidation product. When this center is filled with Fe(III), in bacterial or archaeal ferritin the presence of phosphate accelerates the rate of Fe(II) oxidation. The molecular mechanism underlying this stimulatory effect of phosphate is unknown. Using site directed mutagenesis of the residues in the diiron center of the archaeal ferritin from Pyrococcus furiosus we show that phosphate facilitates displacement of Fe(III) by Fe(II) from this site. Therefore, the rate of Fe(II) oxidation increases only when the ferroxidase center is filled with Fe(III).