Once the novel coronavirus SARS-CoV2 invades a human cell, the crucial next stage is replication, when it creates copies after copies of itself. For this, the virus uses its “copy machine”, which is an enzyme with this function. Trials with various drugs are targeting various stages of virus activity, and some of them, notably remdesivir, seek to inhibit specifically the enzyme that multiplies the genetic material of the virus.
Now, researchers have reported that they have determined the 3D structure of this “copy machine”. This makes it possible to investigate how drugs such as remdesivir work, they note.
How it works
The first stage of infection is the virus entering the human cell. On the surface of the virus is a spike-shaped protein, the so-called “corona”, which binds itself to a human cell enzyme, ACE2. The virus then acidifies compartments on the cell surface, enters, and then begins to replicate using the body’s own mechanism.
SARS-CoV2 is made of a single strand of RNA, which is what is copied and recopied. Enzymes that enable the creation of RNA (or DNA) are called polymerases; in the case of SARS-CoV2, the polymerase is called RdRp, also named nsp12. It is the polymerase whose structure researchers have now described.
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What is new
The 3D structure has been determined by researchers at the Max Planck Institute in Germany, led by director Patrick Cramer, the institute said in a statement.
They reconstituted the polymerase from three purified proteins. Once it was functional in the test tube, they examined the samples under an electron microscope, magnified more than 100,000 times. “One sample looked different, somehow strange. Our first thought was to discard it. Fortunately, we did not: This sample, over all, provided us with the high-quality data we needed,” researcher Dimitry Tegunov said in the statement.
The team reported that in overall architecture, the SARS-CoV2 “copy machine” is similar to that of SARS-CoV, the coronavirus responsible for SARS. However, they also noted distinguishing features. One of these is an additional element in the SARS-CoV2 polymerase, with which it binds the RNA until it has copied the genetic material.
“We were surprised to find that the structure of the coronavirus polymerase is special — it differs from other structures that we have been investigating so far,” researcher Hauke Hillen said.
Why it matters
The researchers repeatedly referred to remdesivir, which work by blocking the polymerase. Their description of the 3D structure comes amid mixed signals from studies on remdesivir. While some trials have found the results encouraging, a study published in The Lancet this week has reported that the clinical benefits from administering remdesivir were not found to be statistically significant.
Knowledge of the architecture of the polymerase on an atomic scale is important, nevertheless, as it opens up new avenues to understand and combat the virus. The team plans to investigate how antiviral substances block the proliferation of coronaviruses.
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“With the structure at hand it might be possible to optimize existing substances such as remdesivir and to improve their effect. But we also want to search for new substances that are able to stop the virus polymerase,” said Cramer, the Max Planck director.
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