Targeting Receptor Tyrosine Kinases on Human Cells Could Be a Game Changer Against COVID-19 Infections

Medical News: In a groundbreaking new study by American scientists from the Department of Veterinary and Biomedical Sciences at the College of Veterinary Medicine, University of Minnesota, a novel approach to tackling SARS-CoV-2 has been uncovered. Instead of targeting the virus directly - a method that often leads to drug resistance - the researchers turned their attention to the virus’s interaction with host cell mechanisms, particularly focusing on cellular structures known as receptor tyrosine kinases or RTKs.

Targeting Receptor Tyrosine Kinases on Human Cells Could Be a Game Changer Against
COVID-19 Infections

These RTKs are vital molecules on the surface of human cells that control critical cellular processes like growth, metabolism, and communication. Previous research has already shown that viruses like influenza exploit RTKs to enhance their replication. In this Medical News report, scientists now reveal that SARS-CoV-2, the virus behind COVID-19, also appears to hijack these same signaling pathways to promote its infection and spread.
 
A New Antiviral Strategy Focuses on Host Cells
The study specifically investigated three types of RTKs - HER2, TrkA, and EGFR - using chemical inhibitors already known from cancer research. The team used two different cell lines: A549-ACE2 human lung epithelial cells, and Vero-E6 monkey kidney cells, both of which are commonly used to study viral infections.
 
They tested four drugs: Lapatinib (HER2/EGFR inhibitor), GW441756 (TrkA inhibitor), Gefitinib (EGFR inhibitor), and AG879 (HER2/TrkA dual inhibitor). Lapatinib and GW441756 showed promising results in the A549-ACE2 cells, significantly reducing viral replication. Notably, Lapatinib was also effective in the Vero-E6 cells, while GW441756 was not.

Lapatinib appeared to disrupt the virus during its entry phase, while GW441756 was more active during the later stages of the viral life cycle, such as replication and protein synthesis. This difference indicates that the HER2 pathway may be involved in the virus’s ability to enter human cells, while TrkA might support the virus once it is already inside.
 
Therapeutic Potential and Time-Sensitive Effectiveness
To better understand the effectiveness of these inhibitors, the researchers conducted time-of-addition experiments using a modified version of SARS-CoV-2 that glows under special conditions, allowing easy tracking of viral activity. These tests showed that Lapatinib had the most impact when applied early, confirming its role in blocking viral entry. On the other hand, GW441756 continued to work well even when added hours after infection, suggesting it acts later in the infection process.
 
Both drugs demonstrated a high therapeutic index in human lung cells, meaning they were effective at concentrations that did not harm the cells. Gefitinib, in contrast, showed little to no antiviral activity and was thus considered ineffective for this purpose.
 
RTKs and Virus Activation Go Hand in Hand r />
Further experiments revealed that SARS-CoV-2 infection actually activates RTK signaling in human cells, especially TrkA and EGFR, which may explain why the virus benefits from these pathways. While HER2 activation wasn’t significantly increased - possibly due to its already high levels in uninfected cells - the data clearly points to RTKs playing a key role in supporting viral infection.
 
These discoveries offer a strong rationale for repurposing existing RTK inhibitors - currently used in oncology - as potential antiviral treatments. Such host-targeted therapies may also be less prone to resistance compared to drugs that directly attack viral components.
 
Conclusion
This study delivers compelling evidence that host receptor tyrosine kinases, specifically HER2 and TrkA, play critical roles in facilitating SARS-CoV-2 infection in lung epithelial cells. Inhibiting these pathways using existing cancer drugs like Lapatinib and GW441756 could open new avenues for COVID-19 treatment strategies that are less vulnerable to viral mutations and drug resistance. While more work is needed to understand their precise mechanisms and validate their effects in clinical settings, the findings mark a promising shift in the fight against current and future coronavirus threats. By focusing on the human body’s own cellular infrastructure, scientists may have found a smarter, longer-lasting strategy to outwit the ever-evolving SARS-CoV-2 virus.
 
The study findings were published in the peer reviewed journal: Pathogens
https://www.mdpi.com/2076-0817/14/4/333
 
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