Each month for the last 20 years, scientist and artist David Goodsell has published the Protein of the Month, showcasing his beautiful renditions of scientifically important and curious proteins. I featured some of his artwork at SynBioBeta’s global synthetic biology summit

Back in February, I reported on the synthetic biology companies racing to fight the coronavirus (it wasn’t even declared a pandemic yet). Since then I’ve reported how companies like Berkeley LightsTwist BioscienceDistributed BioGenScriptSherlock Biosciences, and Mammoth Biosciences have focused their energies on ending the pandemic. All of these stories offer us a big-picture perspective of science versus coronavirus.

Goodsell’s Protein of the Month for September is a chance to go deep on a scientific aspect of the coronavirus, a little protein named nsp-12 that gives SARS-CoV-2 its special power.

nsp12
How can an entire pandemic hinge on one tiny protein? nsp12 gives coronavirus the ability to replicate itself inside human cells. DAVID GOODSELL, PROTEIN DATA BANK

How can an entire pandemic hinge on one tiny protein?

You may remember from biology class that the cells of all living organisms store their genetic information in the iconic double helix of DNA. Unlike cells, viruses have a variety of genome types. Viruses in the Herpes family use the familiar double-stranded DNA molecule, while the Hepatitis D virus is characterized by a circular ball of RNA. The genome of SARS-CoV-2 — the virus that causes Covid-19 — consists of a single strand of RNA. 

Besides storing genetic information, a virus genome also acts as messenger-RNA (mRNA), the transcript that is read by ribosomes in order to make all the protein parts of the virus. When a virus infects a human cell, it hijacks the ribosomes in the cell as its own protein factory to make millions of copies of itself.

virus genome variations.
All possible virus genome variations.K. VAVITSAS

In the case of the Covid-19 virus, however, one human enzyme cannot be used for replicating its own strand of RNA: DNA polymerase. Because SARS-CoV-2 is an RNA virus, it needs an RNA-to-RNA polymerase, so the virus carries its own: the unassumingly named “non-structural protein 12”, or nsp12.

Nsp12 is the RNA polymerase that allows the Covid-19 virus to replicate its genome and wreak havoc on our bodies. Only a few months after the virus’s discovery, several research groups around the world successfully elucidated the protein structure of this important molecule. The researchers used cryoelectron microscopy, a powerful technique where a sample is rapidly frozen and observed under an electron microscope.

Nsp12
Nsp12 in action: the SARS-CoV-2 polymerase (light blue) synthesizes a new RNA molecule (gold) using an existing RNA (red) as a template.
 
K. VAVITSAS, PDB ENTRY: 6YYT

A potential therapeutic target?

Many therapeutic approaches to Covid-19 focus on proteins exposed at the virus’s surface, such as the now-infamous ACE2 ‘spike’ protein. However, targeting the nsp12 polymerase offers several advantages. Because nsp12 is so crucial to SARS-CoV-2’s ability to replicate itself, it is unlikely to mutate over time, making it a stable therapeutic target. Blocking or disrupting nsp12’s interactions with viral RNA will stop proliferation of the virus dead in its tracks, allowing the immune system to fight the disease without the risk of being overwhelmed. Finally, because nsp12 is not a human enzyme, targeting this RNA-to-RNA polymerase will stop the virus from replicating without affecting the patient in any way.

Now that the structure of nsp12 has been characterized, protein modelers can computationally screen thousands of compounds for how they interact with the polymerase. The most promising ones are then tested in protein assays before moving on to clinical trials. Since many other viruses utilize an RNA-to-RNA polymerase — influenza, Ebola, and hepatitis, just to name a few — there already exists a plethora of known antivirals that could block RNA replication in SARS-CoV-2.

Remdesivir, made by Gilead, is one such drug and the only antiviral granted emergency approval to treat Covid-19. Initially developed to treat hepatitis and Ebola, Remdesivir works by mimicking the structure of an RNA base, binding to viral RNA, and blocking replication by a polymerase like nsp12. Several other RNA polymerase blockers function in a similar way, such as Ribavirin, Galidesivir, and Favipiravir. All three compounds, together with Remdesivir, are being used in randomized Covid-19 treatment trials around the world.

Remdesivir
Remdesivir (gold molecule in the center) blocks nsp12 (light blue) from synthesizing a new viral RNA molecule (red).
 
K. VAVITSAS, PDB ENTRY: 7BV2

While we have yet to find the treatment or combination of treatments that works best against Covid-19, the research community is gathering information at unprecedented speed. Scientists modeled the structure of SARS-Cov-2 mere weeks after the outbreak made international news. Now new details of the virus’s components will guide efforts in biotech and pharma to end this pandemic.

Forbes

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