SARS-CoV-2 Cap Offers New Target for Antivirals

The new SARS-CoV-2 viral strain has raised concerns that it may be more difficult to prevent and treat than its predecessor.

 Summary 

Before it can wreak havoc in human cells, the virus that causes COVID-19 must conceal the tip of its genetic material. By diving into how the virus takes on its masquerade, researchers have uncovered a novel technique to attack it.

An examination into how SARS-CoV-2 camouflages itself from cells has exposed a possible weakness in the virus that scientists want to exploit.

Biochemist Vincent Tagliabracci’s group has highlighted critical stages by which SARS-CoV-2, the virus responsible for COVID-19, disguises one end of its DNA. Without this cover-up, the virus can no longer hijack cells to generate an infection. The study team reported their discovery, which has not yet been peer-reviewed, in a preprint uploaded on bioRxiv.org on February 9, 2022.

“If we could create an inhibitor against this camouflage mechanism, it would provide a new strategy to target the virus,” says Tagliabracci, a Howard Hughes Medical Institute Investigator at the University of Texas Southwestern Medical Center.

A number of antiviral drugs to treat SARS-CoV-2 infection, including remdesivir, molnupiravir, and nirmatrelvir, are presently utilized in hospitals and clinics. In other circumstances, physicians may mix various antivirals to deliver a greater punch, while having extra alternatives might come in useful should a virus grow resistant to one medicine.

SARS-CoV-2 Cap Offers New Target for Antivirals


To tackle COVID-19 over the long term, Tagliabracci adds, “we are going to require a mix of antiviral medications that function in diverse ways.”

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SARS-CoV-2’s genome is made of RNA, a molecular relative of DNA. During an infection, the virus gets past human cells’ defenses and fools them into creating new viruses. SARS-CoV-2 utilizes numerous ways to perpetrate this masquerade, including concealing one end of its RNA with a chemical cap, like a spy slipping on a wig. It’s no accident that this covering is similar to the one atop human mRNA, which provides the cell’s protein-making instructions. With a cap in place, SARS-CoV-2 may deceive the cell into constructing viral proteins as if they were its own. While researchers previously understood that the virus depended on its protective cap, they didn’t know how it assumed this disguise.

“If we could develop an inhibitor against this camouflage process, that would represent a new way to target the virus.”

Vincent Tagliabracci, HHMI Investigator at University of Texas Southwestern Medical Center

Tagliabracci’s team analyzes what he terms “weird kinases,” strange members of a broad family of enzymes vital to numerous functions inside the cell. Over the past 35 years, kinases have emerged as major therapeutic targets for illness. Once scientists deciphered SARS-CoV-2’s genome, his team searched through it seeking for kinases, normal or odd. Within the coding for a big multifunctional protein, scientists found a kinase-like enzyme, known as the NiRAN domain.


Building on past studies, Tagliabracci’s team, including graduate students Gina Park and Adam Osinski, put together the steps the NiRAN domain takes to transport viral RNA into position before attaching the cap. When they interfered with NiRAN’s capacity to execute its function, SARS-CoV-2 could not replicate within human cells, the study discovered.


Given the NiRAN domain’s position as an unconventional kinase related, Patrick Eyers, a kinase biochemist at the University of Liverpool, is hopeful about the possibility for novel antivirals. “Kinases are very wonderful pharmacological targets, not only in human cells but in any illness where a kinase is involved,” adds Eyers, who was not part of the research. Scientists have years of expertise designing medications that modify kinase activity in cancer and inflammatory disorders, he adds.


Viral RNA capping has previously caught the interest of researchers seeking novel strategies to battle not just COVID-19, but other viral diseases, says Warner Greene, a virologist at Gladstone Institutes, who was not involved in the study.


But scientists have not yet found success. The key problem is that human cells also cap their mRNA, thus interfering with the virus might have unforeseen repercussions. Tagliabracci’s team has established that the processes SARS-CoV-2 takes to cap its DNA are conducted by viral proteins, “which make them genuine targets,” Greene adds. “But you’ve got to be damned sure there is no overflow into the host proteins that carry out the identical steps.”


The endeavor to find a novel antiviral based on Tagliabracci’s lab’s discovery has already started. His team is currently exploring for tiny compounds that interfere with the virus’s capping process — without hurting human cells.