Human Protein Could be Targeted to Block SAR-CoV-2 Infection

Human Protein Could be Targeted to Block SAR-CoV-2 Infection

A human protein that regulates the angiotensin-converting enzyme 2 (ACE2) receptor could potentially be targeted in a new treatment to prevent SARS-Cov-2 infection.

Infection with the SARS-CoV-2 virus, which causes COVID-19, is initiated by the spike protein of the virus binding with the ACE2 cell surface receptor on human cells. If the spike protein is unable to bind to the ACE2 receptor, the virus is unable to invade host cells.

To identify potentially druggable pathways to prevent infection, a team of researchers at UC San Francisco conducted a targeted CRISPRi screen on 2,325 cellular proteins to identify modifiers of spike binding to human cells. The researchers believe that genes coding for factors that regulate ACE2 expression could potentially be targeted to prevent infection and to reduce the severity of disease if infection occurs, as ACE2 affects the inflammatory responses and is itself regulated in the context of inflammation.

There is currently considerable research being conducted to identify proteins that could potentially be targeted in novel treatments against COVID-19, but in most cases, they are proteins produced by the virus. The researchers have identified a human-produced protein, named BRD2, which could potentially be targeted.

BRD2 is already known to regulate the expression of genes, including those that promote tumor growth in certain cancers. There are clinical trials underway involving the targeting of BRD2 and other associated proteins as potential cancer treatments.

The UC San Francisco researchers discovered BRD2 regulates ACE2 expression in the tissues that are most susceptible to infection such as lung cells, heart cells, and nasal cavity cells. They also found that existing drugs that target BRD2, which are currently being trialed, were effective at blocking infection in susceptible cell types in vitro and in hamsters.

The researchers found that knocking down BRD2 was almost as effective at inhibiting ACE2 production as knocking down ACE2 itself. While the findings of the study are promising, there is still considerable research required to determine if knocking down BRD2 or any other potential drug targets is safe, especially considering knocking down BRD2 also inhibited the production of interferon, a protein critical to the inflammatory response. There could well be side effects of such a treatment on the immune system that could be just as harmful, if not more, than SARS-CoV-2 infection.

You can read more about the study in the paper – BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2 – which was recently published in Nature Cell Biology. DOI: 10.1038/s41556-021-00821-8