Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Abstract

In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.

Keywords: Baricitinib; COVID-19; Cytokine storm; JAK-STAT; Pharmaceutical care.

Fig. 1

The possible mechanisms of baricitinib on cytokine storm caused by SARS-CoV-2. When the human body is invaded by SARS-CoV-2, the immune system will release a large number of cytokines (such as IFN-γ, IL-6 etc.). Excessive amounts of cytokines bind to their receptors and activates JAKs, which occurs upon ligand-mediated receptor multimerization. The activated JAK phosphorylates the receptor, activates and phosphorylates its main substrate STATs. For example, IFN-γ signals via JAK1 and JAK2 which in turn activate STAT1, whereas IL-6 can signal via JAK1, JAK2, and/or TYK2 and activates STAT3. Phosphorylated STAT dimerizes with other members of STAT family. Then, the dimerized STATs in the cytoplasm are transferred into the nucleus and combine to specific DNA elements to regulate the expression of cytokine-responsive genes. Subsequently, cytokine storm was finally induced.