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dcyphr | JAK Inhibition as a New Treatment Strategy for Patients with COVID-19

Abstract

It is important to understand how SARS-CoV-2 infects the cells so that medications and vaccines can be safely developed. This study looks at angiotensin-converting enzyme 2 (ACE2) and Ang 2 receptor-1 (AT1-R). Some treatments involving ACE2 and AT1-R are recombinant ACE2, ACE inhibitors, AR1-R blockers, Ang 1-7 peptides, and Janus kinase-signal transducer inhibitor (JAKinibs).


Background

SARS-CoV-2 causes a wide range of symptoms and severity. It has a high infectivity and mortality rate. Therefore it is vital to understand how the virus works. This is instrumental in the process of developing antiviral medications or vaccines.


Angiotensin-Converting Enzyme 2

ACE2 has been highlighted because SARS-CoV-2 uses it to enter the target cell. ACE2 helps to maintain blood pressure, so it is found in the heart, lungs, kidneys, brain, testes, liver, and small intestines. In normal cells, ACE2 inactivates angiotensin 2 (Ang 2) by cutting it and turning in into Ang 1-7. Ang 2 increases blood pressure, so ACE2 lowers blood pressure when it cuts Ang 2. SARS-CoV-2 finds ACE2 on the outside of a cell and binds to it, which causes a process called endocytosis. In this process, SARS-CoV-2 and ACE2 enter the cell. This causes Ang 2 levels to rise, which will lead to acute respiratory distress syndrome (ARDS). ARDS is fatal for many patients.

One medication strategy could be a medication that binds to ACE2 better than SARS-CoV-2, so the virus can never even enter the cell. There can be issues with this option though-- like the dosing, method of ingestion, and possible side effects. This medication could be effective if it was taken very early on in the course of the viral infection.


Angiotensin 2 Receptors

Ang 2 interacts with a receptor called Ang 2 type 1 receptor (AT1-R) that deals with a lot of cardiovascular and renal functions.  AT1-R blockers (ARBs) have been looked at as a possible treatment for COVID-19, but there are conflicting results of these studies. One study has shown that elderly patients already taking ARBs for high blood pressure may be less likely to have a severe COVID-19 case. ARBS and other medications like recombinant ACE2, ACE inhibitors, and Ang 1-7 peptides may prevent cardiac or lung damage from COVID-19. But, it may be harmful to stop these medications. So, people who are already taking these medications for their underlying health conditions should continue use advised by their health care provider.


ATI-R and Cytokine Signaling through the Janus Kinase-Signal Transducer and Activator of Transcription Pathway in COVID-19

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) is the name of the pathway that Ang 2 uses to function. JAK-STAT is also the pathway that coordinates the different components of the immune system. As Ang 2 levels increase, immune function and inflammation increase in the same area. There are two proposed explanations for this relationship. First, AT1-R activates the JAK-STAT system. The second explanation is for patients with a severe COVID-19 case and is called a cytokine storm, which means a large amount of inflammation causing factors are released by immune cells. Then, the immune system has a bad reaction to all of the inflammation, and causes organ failure.


JAK inhibitors

JAK inhibitors are currently used to treat rheumatoid arthritis. Compared to other JAK inhibitors, Baricitinib may be the most effective against COVID-19. Baricitinib would stop SARS-CoV-2 from assembling and would reduce inflammation in patients with ARDS. Baricitinib can also stop the virus from entering the cell. JAK inhibitors may not be perfect though because they can weaken the immune response too much and affect red blood cell levels. But, antiviral medication like remdesivir coupled with a JAK inhibitor may be very effective. Many other JAK inhibitor medications are going through trials for different immune diseases, with varied results and side effects. JAK is recommended to be given only to those who are hospitalized with severe cases of COVID-19 since 80% of patients can heal with their immune response alone. More studies must be done to confirm JAK inhibitors as a method of treatment for COVID-19.


JAKinib Monotherapy or Combination Therapy with MTX

Methotrexate (MTX) is currently used to treat autoimmune diseases and some cancers. It works through the JAK-STAT pathway to reduce inflammation. MTX is being studied to see if it would be more beneficial when paired with a JAK inhibitor. Some specific JAK inhibitors do show some improvement when taken with MTX, but some studies contradict these trials. These medications cannot tell healthy cells from diseased ones, so researchers and physicians must proceed with caution in pairing these medications.


Conclusion

Targeting ACE2 and AT1-R for the treatment of COVID-19 is promising. However, more studies need to be done on recombinant ACE2, ACE inhibitors, ARBs, and Ang 1-7 peptides as use of COVID-19 treatment. JAK inhibitors may be successful in treating COVID-19 because they reduce lung, heart, and kidney damage while also reducing some inflammation in ARDS patients. The combination of baricitinib and MTX may be the most effective against COVID-19. But, MTX is only needed in a small dose to be effective, so it may be a cheaper and safer option to use alone, without JAK inhibitors. JAK inhibitors tend to be more expensive and have more side effects.