Discovery of rapid COVID-19 replication mechanism could expand treatment options

Concerns about COVID-19 have significantly diminished, but researchers continue to analyze its high transmission rate, aiming to prepare for future infectious diseases. A research team has newly identified the mechanism behind the rapid proliferation of the COVID-19 virus.

Dr. Seong-Jun Kim’s team from the Korea Research Institute of Chemical Technology (KRICT) have reported in a research paper that the rapid proliferation of COVID-19 is due to altered roles of mitochondria and epidermal growth factor receptor (EGFR; responsible for growth signal transmission in cells).

The paper is published in the journal Signal Transduction and Targeted Therapy.

Pandemic-causing coronaviruses, such as SARS in 2003, MERS in 2015, and COVID-19 in 2019, have been repeatedly emerging. Given the increasing frequency of such outbreaks, there is an urgent need to accelerate the response to new infectious diseases.

While numerous studies on COVID-19 have been conducted, focusing initially on the viral entry mechanism and vaccine development, recent research has explored methods to hinder viral replication by altering calcium ion concentrations in cells.

However, the precise mechanism underlying the rapid replication of the virus after it enters human cells has remained unclear. Understanding this process is crucial for future pandemic preparedness.

Dr. Kim’s team revealed that once COVID-19 invades human cells, it quickly modifies the structure and function of mitochondria to abnormally enhance energy production, which is essential for viral replication. They also discovered that the virus manipulates the EGFR protein, which is critical for cellular growth signaling, to maintain this rapid replication.

This increases the likelihood of the virus replicating and spreading in large numbers. Importantly, the team demonstrated through experiments that using EGFR-targeting drugs could effectively treat COVID-19.

The researchers focused on two major phenomena occurring after the virus enters host cells:

• Enhanced ATP production: The viral RNA-nucleocapsid complex influences the mitochondrial membrane potential, leading to abnormal increases in energy production. Mitochondria fusion is promoted, increasing surface area and ATP production efficiency.
• Alteration of EGFR function: COVID-19 infection activates the EGFR signaling pathway, with altered EGFR relocating to mitochondria. This sustains excessive energy production, facilitating rapid viral replication.

Using FDA-approved EGFR inhibitors, such as vandetanib and dacomitinib, the team confirmed significant antiviral effects. Notably, vandetanib was highly effective, reducing viral RNA levels in infected mice by 90% after oral administration for three days and significantly alleviating lung inflammation after six days.

Additionally, the antiviral efficacy of vandetanib against COVID-19 variants such as alpha, beta, delta, and omicron was remarkable, with as much as a 100,000-fold reduction of viral RNA levels in some cases. Vandetanib also effectively prevented the infection of newly produced viral progeny.

The results demonstrate a novel mechanism underlying COVID-19’s rapid replication and suggest the potential for drug repurposing to treat viral infections using existing approved therapies. This discovery could be a significant step toward combating future infectious diseases.

Dr. Kim from the KRICT said, “At a time when we need to prepare for the frequent spread of infectious diseases, the identification of a new mechanism for rapid viral replication and the development of new treatment strategies will contribute to the health and safety of people.”