Key regulators of COVID virus receptors may be new drug targets

Entry of the SARS-CoV-2 virus into human tissues is dependent on the activity of host genes that regulate production of key viral receptors, according to a study published in the open access journal PLOS Biology by Madison Strine and Craig Wilen of Yale University, US, and colleagues.

These findings provide important new information about how the virus that causes COVID-19 causes infection and could lead to new antiviral treatments.

In a previous study, the authors identified the DYRK1A gene as an important gene for the pathogenesis of SARS-CoV-2. The gene encodes a kinase, a type of enzyme, and was previously involved in regulating cell proliferation and neurodevelopment. It has also been shown to promote infection with certain viruses through its enzymatic activity, although the functions of the other proteins appear to be independent of their role as enzymes.

To explore how DYRK1A promotes SARS-CoV-2 infection, the authors removed the gene in cultured cells, and found that they are less susceptible to infection, specifically by reducing viral entry into target cells. The main entry point for the virus is the receptor, ACE2.

The authors demonstrated that disabling DYRK1A reduces ACE2 activity. When they reintroduced DYRK1A using the gene vector, cells once again activated ACE2 and became susceptible to viral infection. That vulnerability was independent of DYRK1A’s enzymatic function, they found, because introducing a mutant DYRK1A without enzyme activity, or blocking enzyme activity pharmacologically, still led to infection.

Previous studies revealed that, in addition to acting as an enzyme, DYRK1A functions as a transcription factor, altering the activity levels of various genes. In this study, the authors show that loss of DYRK1A downregulates ACE2, along with the gene for another receptor, DPP4, which is the entry point for a related virus, MERS-CoV.

Inhibits the entry of viruses

Reducing DYRK1A reduces chromatin accessibility near the transcription start site of ACE2, along with several other sites known to increase ACE2 gene activity. Without high levels of ACE2 on target cells, viral entry is inhibited.

“New therapeutic targets against current and future coronaviruses are needed to combat drug resistance and emerging viruses,” Strine said.

Although small molecule inhibitors of DYRK1A exist, “these drugs are limited by their limited selectivity and toxicity. Moreover, this inhibitor structurally targets the catalytic function of DYRK1A, which we have now shown cannot be used for coronavirus entry. Therefore, consideration of DYRK1A as a therapeutic target will require a new drug class that can tolerate and limit DYRK1A activity irrespective of its catalytic function.”

Wilen added: “We identified a host protein called DYRK1A which is critical for activating receptor expression for several highly pathogenic coronaviruses including the viruses that cause SARS, COVID and MERS. This gives us important insight into what makes species, tissues and cells susceptible to the coronavirus.”