Thursday, October 22

One more step towards new drugs against COVID

The clinical course of COVID-19 is extremely variable from one person to another: while most infected people have no symptoms or very few, others instead develop very serious complications that can lead to them. death.

These differences indicate that in addition to the virus itself, certain factors associated with the host play a very important role in the severity of the disease.

Studies to date indicate that age, male gender, and the presence of comorbidities (obesity, diabetes, cardiovascular disease, and cancer) are among the major risk factors for complications, but the biochemical reasons for these factors provide the virus with an environment that amplifies its infectious potential are still poorly understood. Recent research sheds some of the mystery behind these links.

Molecular targets

To better understand what these severe Covid-19 cases correspond to at the molecular level, a team of American researchers has therefore analyzed in detail the biochemical composition of 128 blood samples taken from patients hospitalized for respiratory problems (1).

One hundred and two of these patients tested positive for COVID-19, while the remaining 26 were negative and therefore served as a control. Using cutting-edge biochemical analysis methods (RNA sequencing and mass spectrometry), researchers were able to quantify more than 17,000 different proteins, metabolites, lipids and genes, and to measure how the levels of these molecules varied. depending on the severity of COVID-19, a titanic job!

This approach has identified 219 molecular characteristics associated with severe COVID-19, which can be classified into three main categories:

1) Disruption of inflammation. The analysis revealed high levels of proteins and genes involved in the degranulation of neutrophils, the process by which these immune cells release a wide variety of proteins intended to break down an infectious agent.

Too much degranulation is typically associated with the development of excessive inflammatory conditions, a phenomenon that has been repeatedly associated with the severity of COVID-19.

2) Coagulation disorders. A large number of patients affected by COVID-19 present with abnormal formation of blood clots (hypercoagulation) and the study shows that these disorders are correlated with variations in several elements of the coagulation cascade.

Note in particular a decrease in citrate, a product of cellular metabolism which is known for its anticoagulant action, and in gelsolin, a protein endowed with a powerful anticoagulant action.

3) Damage to blood vessels (endotheliopathies). The study also showed that several proteins involved in the response to damage to the integrity of blood vessels were increased in patients with COVID-19, especially severe forms of the disease.

The blood vessels have large amounts of the receptor that allows the virus to enter cells (ACE2) and multiple viral particles have been observed in the blood vessels, as well as extensive damage to the structure of these cells. cells (2).

Molecular signature

This ability of the virus to specifically target blood vessels would explain why people with pre-existing heart disease or conditions that affect the health of blood vessels (diabetes and hypertension, for example) are much more at risk of developing severe complications from COVID-19.

The molecular signature of COVID-19 sketched by this study clearly shows how this infectious disease presents a unique clinical profile, capable of causing serious failures by affecting several physiological systems essential to life.

As the authors point out, the identification of the main molecules affected by the virus will make it possible to identify new therapeutic targets and lead to the development of revolutionary treatments, with new drugs attacking these targets. Biochemistry is in the midst of the coronavirus war!

Overmyer KA et al. Large-scale multi-omic analysis of COVID-19 severity. Cell Systems, released October 6, 2020.

Ackermann M et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N. Engl. J. Med. 2020; 383: 120-128.

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