>>14720984 (/pb)
Theoretical analyses in new areas may necessarily entail reasonable speculations based on limited or disparate data. This is expected, but one should remain cognizant of overinterpretation, and pursue a rational course of theoretical inquiry to hopefully inform subsequent experimental investigations. Here, a purposeful and restricted protein sequence search revealed a potential sequence similarity between the relatively less-studied cysteine-rich cytoplasmic domain of coronavirus spike proteins and the vertebrate hepcidin protein. This is quite unlikely to be a spurious and random similarity. There are many cysteine-rich protein sequences in vertebrates, but the motif identified here is unique and specific, and also appears to tentatively set apart the disease-causing strains from the milder coronavirus strains. Following from this link, a number of emerging clinical strands of evidence (summarized in Table 1) were discussed which further link a biology surrounding hepcidin with coronavirus-caused pathobiology. While each piece of clinical evidence discussed does not by itself provide overwhelming corroboration for the hypothesis of the paper, the totality of evidence presented we believe make a strong case that if sequence and/or structural mimicry to hepcidin is taking place upon viral attachment to and entry in the host cell, then perhaps a local disease condition resembling iron dysregulation (e.g., iron overload) might ensue in the infected tissue(s). This hypothesis can be immediately tested in one of three ways. First, in the clinic, levels of various serum markers for iron biology could be more systematically and comprehensively measured and analyzed. This strand of investigation has already produced corroborating evidence in the form of increased serum levels of hepcidin and significantly lower levels of serum iron in COVID-19 patients. Second, computational investigations could examine potential structural mimicry between the two proteins and explore the effect of differing post-translational modifications. And third, the potential link to hepcidin could be relied upon in cell-based assays to determine the possibility of the involvement of the spike protein in iron biology.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7563913/