Aqsa, Jamia Millia Islamia
The causative agent of the current pandemic is the Severe Acute Respiratory Syndrome (SARS-CoV), belonging to a large family of viruses called Coronaviruses. The incubation period for COVID-19 is roughly 14 days. In an infected person, the symptoms usually appear five days after the initial infection. A very small percentage of COVID-19 patients experience hyper-inflammation. The inflammation is caused by an increased amount of cytokine production. Although, the pathway of this process is not clearly understood.
Now, this virus is still underway.
Recent research by Chan, Marina, et al. attempted to provide a successful treatment for the COVID-19 virus. It has been observed that in cases of acute infection, monocytes and macrophages produce cytokine in a large amount. The release of cytokines in patients leads to viral load, loss of lung function, and lung injury. Using machine learning-based modelling, it was found by the researchers that ponatinib could be used to inhibit cytokine release in monocytes in vitro.
The Study
When a patient gets infected with the COVID-19 virus, a series of events follow up. Some myeloid cells, like monocytes and macrophages, produce cytokine in a large amount. The secreted cytokine includes the release of IL-6, IL1b, CXCL10, CCL7, and other inflammatory molecules. It is observed that the N-terminal domain of the spike protein induces multiple inflammatory molecules such as cytokines in myeloid cells. Phenotypic screening along with machine learning-based modelling helped in identifying several protein kinases. The protein kinases such as JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, play an important role as a downstream mediator of N-terminal-domain induced cytokine production. Hence, it was concluded that these protein kinases play an essential role in multiple signalling pathways in cytokine release. Several FDA-approved drugs such as ponatinib and cobimetinib were tested as potent inhibitors of the NTD-mediated cytokine release. Out of these, Ponatinib was found to be the most potent inhibitor. It successfully inhibits all cytokines in response to NTD from Covid-19 as well as other variants.
Results obtained from the study
The machine learning-based approach predicted 428 kinases inhibitors and 91 thousand two-drug combinations. All these drugs could inhibit N-terminal domain-induced cytokine production in Covid infection. It also led to the discovery of several kinases involved in cytokine release. This study suggests that targeting multiple host kinases involved in Covid-19 mediated cytokine production leads to effective treatment. An FDA-approved, Ponatinib is found to be a potent inhibitor of cytokine production. It successfully inhibits cytokine production in response to the NTD from Covid-19 as well as other variants. The duration of treatment of the Ponatinib drug takes a much shorter time in Covid patients when compared to those in cancer patients.
Ponatinib- the most potent inhibitor
The study concluded Ponatinib to be the most potent inhibitor. It successfully inhibits all cytokines in response to NTD from COVID-19 as well as other variants. Other FDA-approved drugs such as cobimetinib, sunitinib, and bosutinib were also identified to be inhibitors in this study. These drugs can also be used for effective treatment and alternative treatment for COVID-19. These drugs successfully help in eliminating life-threatening symptoms.
Also read: Denying manganese availability for pneumonia causing bacteria holds promise for novel antibiotics
References : Chan, Marina, et al. “Machine Learning Identifies Molecular Regulators and Therapeutics for Targeting SARS-CoV2-Induced Cytokine Release.” Molecular Systems Biology, vol. n/a, no. n/a, Aug. 2021, p. e10426. embopress.org (Atypon), https://doi.org/10.15252/msb.202110426.
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Very well explained.