- This study suggests that structural and transcribed proteins of the virus may attack the β1-chain of hemoglobin leading it to release its porphyrin (just like the heme oxidase)1, 2.
- It also suggests that the virus can capture the free porphyrin and use it to enter the human cells, rather than only using the ACE2 and spike protein binding as current studies suggest1.
- This attack leads to:
- Less hemoglobin carrying O2 and CO21,2
- Intense inflammation in the lung cells due to the inability to exchange O2 and CO2, which could explain the ground-glass-like opacities1.
- Alterations in the normal heme anabolic pathway1
- Chloroquine and Favipiravir seems to be able to inhibit in certain extent the virus ability to attack heme and bind porphyrin1.
Current structural and viral properties of the novel coronavirus:
- The coronavirus possesses structural proteins : S (spike) protein, E (envelope) protein, M (membrane) protein and nucleocapsid phosphoprotein, as well as non-structural transcribed proteins : ORF1ab, ORF3a, ORF6, ORF7a, ORF10 and ORF8, that may play a role in the virus capability in infecting human.
- The novel coronavirus is highly homologous to the coronavirus in bats and has some homology with SARS-CoV.
- A certain paradox about its way to enter human cells is emerging in the scientific community:
- Current theories suggest that the virus binds the human ACE2 receptor to its S protein and enters the human cell in the form of phagocytosis.
- Since it’s highly contagious, it is suspected that the ACE2 and S protein should have strong binding ability.
- However, reports in literature show that this ability is weak. Therefore, this study suggests that virus links to porphyrin may play a role in penetrating the human cells via the membrane glycoproteins and E proteins.
Current knowledge about the inflammation biochemical markers in infected patients:
- Abnormal hemoglobin-related biochemical parameters are seen:
- Hemoglobin and neutrophil counts of most patients show a decrease over time.
- Increasing values of ferritin, ESR, CRP, albumin and LDH are noted.
- Therefore, it is suspected that the patient’s hemoglobin is decreasing, and heme is increasing, leading the body to accumulate too many iron ions which lead to inflammation. Ferritin is therefore produced by cells to bind the free iron ions.
- As a reminder, heme contains iron atoms, which has more affinity for O2 in its divalent state and for CO2 in its trivalent states. Binding of O2 to heme oxidize the iron so it becomes trivalent. As it releases O2 to the body cells, iron is reduced to divalent and ready to capture O2 in the lung. When heme is metabolized, the iron atom is recycled, and the porphyrin is transformed into bilirubin.
About the virus abilities to interact with heme and porphyrin:
- ORF1ab, ORF10 and ORF3a seems to have the capability to attack the heme (on its 1-beta chain) leading to dissociation of the iron atom from the heme and releasing of porphyrin, just like the normal human heme oxidase does.
- ORF8 and surface E2 glycoprotein of the virus seems to have the capability to form a complex with porphyrin, capturing it and using it to enter human cells.
- This attack leads to:
- Less hemoglobin carrying O2 and CO2.
- Intense inflammation in the lung cells due to the inability to exchange O2 and CO2, which could explain the ground-glass-like opacities.
About the potential benefit of Chloroquine and Favipiravir:
- Chloroquine could inhibit surface glycoproteins and ORF8 binding to porphyrin to a certain extent, and therefore preventing the complex formation. It could also prevent ORF1ab, ORF3 and ORF10 from attacking the heme and release porphyrin.
- Favipiravir could inhibit the E2 protein and ORF7a protein binding to porphyrin to a certain extent, and therefore prevent the virus from entering the host cells and catching free porphyrins. The binding power of Favipiravir to the virus E2 glycoprotein, ORF7a and ORF1ab is greater than the binding power of the virus to heme or porphyrin.
This experimental study was done by analyzing the protein sequences (downloaded from NCBI and de PDB database) and using multiple modeling tools to identify the potential interaction between the virus structural proteins with the porphyrin and b-heme chain. They compared the docking properties of normal porphyrin-heme liaisons to structural and nonstructural proteins of the virus to porphyrin. The same concept was applied to investigate the possibility of the virus attacking the heme chains.
We expect more litterature to emerge, and an update will follow!
- Wnzhong L., Hualan L. (March 30, 2020). COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv. https://doi.org/10.26434/chemrxiv.11938173.v5
- Loh D. (April 5, 2020). COVID-19, ARDS & Cytokine Storms – The Recycling of Ascorbic Acid by Macrophage, Neutrophils and Lymphocytes. Acquista Ora. https://www.evolutamente.it/covid-19-ards-cytokine-storms-the-recycling-of-ascorbic-acid-by-macrophages-neutrophils-and-lymphocytes/
- Schaecher S., Pekosz A. (2010). SARS coronavirus accessory gene expression and function. In Molecular Biology of the SARS-Coronavirus (pp. 153-166). Springer Berlin Heidelberg. https://doi.org/10.1007/978-3-642-03683-5_10