A review study of targeting of AAK1 and JAK1/2 using baricitinib in COVID-19 infected human cells

The outbreak of a current public health coronavirus 2019 disease is a causative agent of a serious acute respiratory syndrome and even death. COVID-19 has exposed to multi-suggested pharmaceutical agents to control this global disease. Baricitinib, a well-known antirheumatic agent, was one of them. This article reviews the likely pros and cons of baricitinib in attenuation of COVID-19 based on the mechanism of drug action as well as its pharmacokinetics. The inhibitory effect of baricitinib on receptor mediated endocytosis promoter, AKK1, and on JAK-STAT signaling pathway is benefacial in inhibition of both viral assembling and inflammation. Also, its pharmacokinetic has encouraged the physicians toward the drug selection for COVID-19 treatment. On the other hand, most of baricitinib side effects are dosedependent. In conclusion, targeting of AAK1 and JAK1/2 using baricitinib has predicted to be potential and effective with minimal side effects in management COVID-19 infected patients for a short therapeutic dosing period. Laboratory monitoring should be considered for some parameters. However, experimental trials are mandatory for a long-term treatment with a lower dose of baricitinib to evaluate its effectiveness and safety in patients with moderate COVID-19 infection.


INTRODUCTION
The present coronavirus disease 2019 is a leading cause of a serious acute respiratory syndrome which has been announced as a pandemic on March 11, 2020 by the World Health Organization. This novel virus has the ability to infect respiratory, gastrointestinal, and central nervous systems (1) of both human and animals.
Further, coronavirus disease is a highly contagious with a 2% mortality rate. In spite of utilization of mechanical respiratory help, certain supplemental vitamins, and other drugs there is still lack of a particular COVID-19 treatment.
Baricitinib is an oral selective Janus Kinase (JAK 1) and (JAK2) inhibitor (2,3) . It has been acquired approval in more than forty countries for moderate to severe active rheumatoid arthritis as a mono-or combined therapy. Some previous studies have been suggested the application of baricitinib for patients infected with COVID-19 (4,5). Herein, it has been reviewed the databases published in PubMed and Google Scholar using "baricitinib" and "COVID-19" as a search keywords for collection of the required references from inception till June 30, 2020.

What are the objectives of this review?
This review is needed in order to establish the

COVID-19 pathogenesis
Coronavirus 2019 enters host respiratory epithelial cells through receptor-mediated endocytosis mechanism using a protein expressed on its own spike, a surface viral glycoprotein, to bind to the host angiotensin converting enzyme 2 (ACE-2) receptor, a cell membrane bound aminopeptidase receptor which expressed fundamentally in mature lung type II alveolar cells (6) and further in oral cavity mucosa (7) . Furthermore, cyclin G associated kinase serves as another endocytosis regulator.

Why baricitinib?
Baricitinib was selected as one of the suggested agents for COVID-19 treatments and was predicted to diminish the viral ability to infect host respiratory cells due to its inhibitory action on AAK1 associated endocytosis with high binding affinity, also it has binding ability to  From the other hand, it is found that the incidence of herpes zoster and other serious infections was small and near to that of placebo when used for more than fifty two weeks' dosing. Notably, these infections were reported to be more in patients who used 4 mg baricitinib dose than who administered the lower dose. It has been found that there is increment in the mean absolute lymphocyte count in the first month of baricitinib administration but this count has been returned to baseline level with prolongation of therapy. Interestingly, lymphocyte count alterations showed to be within normal range in most patients (17).
Baricitinib therapy associated with initial decrease in the concentrations of hemoglobin but this reduction has been revealed to be transient.

A marked increase in parameters related
to lipids has been considered with this medication, particularly with higher dose (4mg) but this abnormal change in lipid parameters has been at plateau at week 12 (18) and then returned to be stable (19) .
Additionally, according to the animal studies, utilization of baricitinib is contraindicated in pregnancy as animal studies have exhibited embryotoxicity (20) .
The recent retrospective, observational, multicenter, longitudinal study in an one hundred and thirteen hospitalized patients provided a motivated results and concluded that baricitinib is an effective and safe therapy in moderate COVID-19 pneumonia patients (21) . Furthermore, the outcomes of utilization of baricitinib therapy in Northern Italy patients with mild-moderate COVID-19 has been reported that there is a rapid reduction in plasma levels of interlukine-6 and C-reactive protein along with improvement in clinical, viral, and radiological measurements (22,23) .