Virus Coverup: SARS-CoV-2 Cap Offers New Targets for Antivirals

Overview

The virus that causes COVID-19 must hide the tip of its genetic material before it can cause havoc in human cells. By investigating how the virus performs this disguise, researchers have identified a unique way to combat it.

Investigating how SARS-CoV-2 camouflages itself from cells reveals a potential vulnerability in the virus that scientists want to exploit.

Biochemist Vincent TagliabracciIn our laboratory, we explained the important procedure for SARS-CoV-2, the virus responsible for COVID-19, to disguise one end of the genome. Without this concealment, the virus would not be able to hijack cells and cause infection. The research team has conducted their research, which has not yet been peer-reviewed. Preprint Posted on bioRxiv.org on February 9, 2022.

“If we could develop an inhibitor of this camouflage process, it would be a new way to target the virus,” said Tagria Blatch, a researcher at the Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center. ..

A small number of antiviral drugs for the treatment of SARS-CoV-2 infections, such as remdesivir, molnupiravir, and nilmatrelvir, are currently used in hospitals and clinics. In some cases, doctors can combine multiple antiviral drugs to get a stronger punch, but if the virus becomes resistant to one drug, it would be useful to have additional options. ..

To combat COVID-19 in the long run, Tagliabracci states, “We will need a combination of antiviral drugs that work in different ways.”

The SARS-CoV-2 genome is composed of RNA, the molecular cousin of DNA. During infection, the virus bypasses the defenses of human cells and tricks them into producing more viruses. SARS-CoV-2 performs this subtlety using several strategies, such as covering one end of RNA with a chemical cap, like a wig-sliding spy. It is no coincidence that this cover is identical to the cover on human mRNA that contains the cellular protein production instructions. With the cap on, SARS-CoV-2 can trick cells into assembling viral proteins as if they were themselves. Researchers already knew that the virus depended on its protective cap, but did not know how this disguise was done.

“If we could develop an inhibitor of this camouflage process, it would be a new way to target the virus.”

Vincent Tagliabracci, HHMI Researcher, Southwestern Medical Center, University of Texas

Tagliabracci’s lab is studying what he calls a “strange kinase.” It is a strange member of a large family of enzymes that are essential for many intracellular processes. Over the last 35 years, kinases have emerged as important drug discovery targets for the disease. When scientists deciphered the SARS-CoV-2 genome, his team scrutinized it for normal or bizarre kinases. Within the code for large multifunctional proteins, they recognized a kinase-like enzyme known as the NiRAN domain.

Based on previous studies, Tagliabracci’s team, including graduate students Gina Park and Adam Osinski, summarized the steps that the NiRAN domain takes to move viral RNA into place before adding a cap. rice field. The team discovered that SARS-CoV-2 was unable to multiply within human cells when they interfered with NiRAN’s ability to work.

Given the status of the NiRAN domain as an unconventional kinase relative, Patrick Eyers, a kinase biochemist at the University of Liverpool, is optimistic about the outlook for new antivirals. “Kinsases are truly great drug discovery targets, not just in human cells, but in any disease involving kinases,” said Iars, who was not involved in the study. Scientists say he has years of experience in creating drugs that alter the kinase activity in cancer and inflammatory conditions.

Viral RNA capping has already attracted the attention of researchers looking for new ways to combat COVID-19, as well as other viral infections, said a virologist at the Gladstone Institutes who was not involved in the study. One Warner Green says. But scientists haven’t succeeded yet. The main challenge is that human cells also cap mRNA, so interference with the virus can have unintended consequences. Tagliabracci’s team has shown that viral proteins carry out the steps SARS-CoV-2 takes to cap its genome. This “makes them a legitimate target,” says Greene. “But you need to make sure there is no spillover to the host protein that performs the same steps.”

Based on the findings of Tagliabracci’s lab, work has already begun to identify new antivirals. His team is currently looking for small molecules that interfere with the virus’s capping mechanism without interfering with human cells.

###

HHMI scientists are working with many of our colleagues around the world to combat the new coronavirus. They develop diagnostic tests, understand the basic biology of the virus, model epidemiology, and develop potential therapies and vaccines.We will be Share some stories of this work..

Quote

Gina J. Park, Adam Osinski and others “”Mechanism of RNA capping by SARS-CoV-2.. Posted on bioRxiv.org on February 9, 2022. doi: 10.1101 / 2022.02.07.479471