New Insights into Human Proteins Essential for Coronavirus Replication Suggest Innovative Treatment Approaches

Despite ongoing vaccination efforts and existing treatments, SARS-CoV-2—the virus responsible for COVID-19—remains a significant global health concern, especially due to new variants and the virus's ability to manipulate human cellular mechanisms. Recent research from The Scripps Research Institute has identified numerous human proteins crucial for the virus's entire life cycle, from cell entry to viral replication and release.

Published in PLOS Biology, this groundbreaking study utilized genome-wide small interfering RNA (siRNA) screening to pinpoint human genes that SARS-CoV-2 depends on. This technique systematically inhibited individual human genes in susceptible cells, revealing essential host proteins that facilitate viral replication. The researchers discovered 32 proteins vital during the early infection stages and 27 involved in later stages, along with specific cellular pathways exploited by the virus, many of which were known, and others newly identified.

Lead researcher Sumit Chanda emphasized the shift in focus from targeting the virus directly to understanding host-virus interactions. This approach opens pathways for developing broad-spectrum antivirals targeting human proteins, potentially effective against various coronaviruses, including future strains, with less risk of resistance development.

Among the identified proteins, perlecan stood out as a promising drug target. This large protein, embedded in the extracellular matrix, was found to interact directly with the virus's spike protein, aiding in cell attachment and entry. Blocking this interaction could prevent infection initiation. Another promising target, BIRC2—a protein involved in inflammation pathways—was successfully inhibited in cell cultures and animal models using Smac mimetics originally developed for cancer and HIV therapy, leading to significant reductions in viral levels.

The study also evaluated the role of these proteins across other coronaviruses like SARS-CoV-1, MERS-CoV, and seasonal coronaviruses. Seventeen proteins were consistently used by all tested viruses, including those involved in cellular fusion, replication, and exit. This indicates that host-targeted therapies could offer a universal approach to combat current and future coronaviruses, reducing the likelihood of resistance linked to mutations.

Plans are underway to explore whether these host proteins are exploited by other respiratory pathogens like influenza and respiratory syncytial virus (RSV). Continued research will focus on the safety and efficacy of potential drug candidates targeting these human proteins.

This research highlights the importance of host-focused strategies in antiviral development, which can provide a higher barrier to resistance and offer the potential for broad-spectrum antiviral agents against multiple coronavirus strains.