Chinese researchers have explained the negative mechanism of SARS-CoV-2 and the associated effectiveness of the two drugs

The causative agent of coronavirus SARS-CoV-2 with the help of non-structural proteins damages hemoglobin, an important transport protein in humans. This leads to increased inflammation and the appearance of “frosted glass” in the lungs.

A study conducted by Wenzhong Liu from Sichuan University of Science and Technology, together with Hualan Li from Yibin University, shows that the SARS-CoV-2 virus can attack human red blood cells by binding to hemoglobin molecules. This leads to disruption in the transport of oxygen through the bloodstream. The article of scientists is published in the archive of preprints Chemrxiv.

Hemoglobin is a complex metal-containing protein that can reversibly bind to oxygen. At the center of each hemoglobin molecule is heme, or the porphyrin core containing a ferrous atom: it is able to bind four O molecules2. Collecting oxygen in the lungs, red blood cells with the help of hemoglobin transfer it to various organs and parts of the body.

SARS-CoV-2 viral particles do not interact directly with red blood cells. A number of non-structural (not part of the viral capsid) proteins encoded by viral RNA are responsible for this. Such proteins facilitate the fixation and replication of the virus in the host organism, blocking cellular mechanisms and biochemical pathways.

Chinese scientists have found that some of these non-structural viral proteins penetrate red blood cells and displace iron from porphyrin nuclei. This makes red blood cells less able to transport oxygen. Researchers were able to identify three such proteins – orf1ab, ORF10 and ORF3a, the binding of which to the beta chain of the hemoglobin molecule leads to the dissociation of iron. Also, surface viral glycoprotein and ORF8 protein may be involved in heme binding.

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The chemical structure of the porphyrin core of the hemoglobin molecule / © Chemed

Such an effect leads to an increase in inflammatory processes in the lungs, hypoxemia, the development of symptoms of acute respiratory distress symptom (ARDS) and multiple organ oxygen deficiency. The binding of viral proteins to heme also explains the occurrence of the so-called frosted glass symptom in asymptomatic coronavirus patients: it is manifested by a decrease in the transparency of the lung tissue due to a decrease in the airiness of the alveoli and the accumulation of hemoglobin in the alveoli. Another symptom that indirectly indicates the effect of the virus on the porphyrin core is an increase in the blood of some patients with the iron-containing protein ferritin.

A new discovery explains the effectiveness of two drugs – hydroxychloroquine and favipiravir – in the treatment of Covid-19. Not so long ago, French scientist Didier Raoul said that more than 1000 people have been cured of coronavirus infection thanks to the use of hydroxychloroquine (which is usually used to treat malaria). According to Liu and Li, chloroquine (the chemical precursor of hydroxychloroquine) can block the attack of the orf1ab, ORF3a, and ORF10 proteins and also prevent the binding of ORF8 to hemoglobin. This allows you to reduce the negative impact of viral infection on the lungs and the body as a whole.

As for favipiravir – this antiviral drug, successful in the fight against many RNA viruses, shows a more directed action against SARS-CoV-2. It blocks surface glycoproteins and the viral protein ORF7a, preventing the virus from entering the cell, and its proteins – modifying hemoglobin molecules.

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The viral protein binding mechanism described by Li and Liu may underlie the phenomenon that children are more likely to tolerate coronavirus infection. As mentioned above, viral proteins cause iron dissociation through interaction with the hemoglobin beta chain, which is a structural part of ΗbA – normal adult hemoglobin. In children, the so-called fetal hemoglobin ΗbF prevails in the blood, which does not contain beta chains and is probably invulnerable to viral proteins.

Perhaps a similar feature in the structure of hemoglobin causes a low incidence in some countries in Africa. In regions where malaria is prevalent, there is a high proportion of people with thalassemia, a genetic disease whose carriers synthesize mutant hemoglobin without beta chains.

The findings of the researchers may lead to a review of the tactics of treatment of severe patients with Covid-19. Probably, protocols for lung ventilation and respiratory support for ARDS can harm coronavirus pneumonia patients, causing lung damage. If the conclusions described in the article are correct, blood transfusion and hyperbaric oxygenation of patients can be of greater benefit.

The work of Chinese scientists is still awaiting review, and the correctness of the conclusions should be confirmed by other researchers. The authors of the work also strongly recommend not to try to start treatment with favipiravir and hydroxychloroquine on their own, and to use these drugs only as directed by a doctor.

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