COVID-19 Update – The Kinase Connection

Vaccines are a critical factor for stopping the SARS-CoV-2 pandemic as vaccines will help protect uninfected individuals, contribute to herd immunity, and restrict the spread of the virus. However, even after successful vaccines are developed it could take years to manufacture hundreds of millions of doses, to distribute them throughout the world, and to vaccinate the billions of people on our planet. In the meantime, millions will continue to be infected and the world will need antiviral drugs to treat seriously ill patients. Some drugs, such as remdesivir, are already being used for treatment while several other drugs are being tested. However, remdesivir which acts to block viral replication has modest effectiveness and doesn’t limit viral-induced pathologies such as the dangerous cytokine storm. What is needed to treat the wide range of clinical issues appearing in patients is more diversity in drug targets and greater drug efficacy. A paper published last week in the journal Cell identified a promising new set of targets for SARS-CoV-2 drug therapy called kinases.

Kinases are enzymes in our cells that modify proteins by attaching a phosphate group in a process known as phosphorylation. Depending on the specific protein, phosphorylation can turn its activity on or off, much like a light switch can be either on or off. It’s much quicker and more energy-efficient for the cell to regulate protein activity through phosphorylation rather than by increasing or decreasing the amount of the protein itself. This ability to control protein function in our cells make kinases critically important regulators of many biological processes from growth and cell division to immune responses. There are 518 known human kinases, though less than 100 have been well-characterized for their biological function.

Many viruses reprogram cellular kinases to alter the cellular environment so that it favors viral reproduction and spread. In the Cell paper, a large collaboration of international scientists looked at the global effect of SARS-CoV-2 infection on 97 well understood cellular kinases. They found that 49 of these 97 kinases had altered activity in SARS-CoV-2 infected cells, including 3 with particularly interesting links to viral disease: casein kinase II (CKII), the p38/MAPK kinase pathway, and the cyclin-dependent kinases (CDKs). CDKs are a family of kinases that control the cell cycle and are critical for normal cell growth. In SARS-CoV-2 infected cells the CDKs become less active, suggesting that the virus is stopping cell division to shift the cell resources into viral production. The p38/MAPK kinase pathway is involved in the production of inflammatory cytokines. This pathway is more active in the infected cells and could be contributing to the development of the cytokine storms. Lastly, the CKII kinase was activated by infection and was shown to stimulate the development of cell-surface tendrils known as filopodia. Other viruses use filopodia as pathways for virus particles to travel from the infected cell to other surrounding uninfected cells, and SARS-CoV-2 may likewise use this route to spread from cell to cell. No other coronavirus uses this filopodia mechanism, so this would be another unique and novel feature of SARS-CoV-2.

What is most medically relevant about this kinase study is the existence of numerous kinase inhibiting drugs that are already being used clinically, particularly in cancer treatments. The Cell study tested 68 available kinase inhibitors for anti-viral activity against SARS-CoV-2 in cell culture and identified several that were effective against this virus. Clinical trials are already planned to test if individual kinase inhibitors or combination cocktails can shorten infections and/or reduce associated damage to the patient’s various organs. Hopefully, we will have new and better anti-COVID drugs in the near future.

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