Identifying Host Proteins in SARS-CoV-2's Replication Process Uncovers Potential Treatment Points

Scientists at Scripps Research have made a significant breakthrough in understanding how SARS-CoV-2, the virus responsible for COVID-19, completes its replication cycle. They have identified dozens of human proteins that the virus relies on for its replication.

The team used genome-wide siRNA screening to uncover these human proteins. The study, published in PLOS Biology in the paper titled, "Global siRNA screen identifies human host factors critical for SARS-CoV-2 replication and late stages of infection," revealed common pathways like regulation of Wnt signaling and gap junctions, as well as newly discovered pathways like NADH oxidation.

Two proteins identified as potential drug targets are the coronavirus main protease (Mpro) and the papain-like protease (PLpro). These proteins play crucial roles in viral replication and immune evasion.

Another potential drug target is Baculoviral IAP Repeat Containing 2 (BIRC2). It is part of a cellular inflammation pathway and can be inhibited by drug compounds known as Smac mimetics, reducing viral levels in animal models. Drug compounds like Smac mimetics, originally developed for cancer treatment and HIV activation, have shown success in inhibiting BIRC2 in SARS-CoV-2 infected cells and mice.

The large extracellular matrix protein perlecan is another potential drug target. SARS-CoV-2's spike protein can latch onto perlecan, potentially suggesting a co-receptor role for perlecan in the virus's infection process.

The findings could lead to new drugs that target host proteins instead of the virus. Blocking human proteins that viruses depend on could form the basis of drugs effective against multiple coronaviruses. In fact, of the 47 human proteins tested against three other coronaviruses (SARS-CoV-1, MERS-CoV, and a seasonal coronavirus), 17 were consistently used by all three viruses.

These potential new treatments may be effective against SARS-CoV-2 and other coronaviruses. If antivirals are ready ahead of time, they could be deployed early in a future coronavirus outbreak, providing a higher barrier to resistance and the potential to block multiple viruses with a single therapy.

The research team plans to explore whether the same host proteins are also used by other respiratory pathogens such as influenza and RSV. This could open up new avenues for developing broad-spectrum antiviral therapies.

As SARS-CoV-2 continues to infect people worldwide, these discoveries bring hope for more effective treatments and potentially a higher level of protection against future pandemic coronaviruses. Over the past month, the United States has recorded approximately 750 deaths from COVID-19. It is crucial to continue supporting research efforts to combat this global health crisis.

Identifying Host Proteins in SARS-CoV-2's Replication Process Uncovers Potential Treatment Points