April 28, 2020

Rochester research into RNA structure and function provides key information for developing coronavirus treatments.

Viruses like the coronavirus that causes COVID-19 are able to unleash their fury because of a devious weapon: ribonucleic acid, also known as RNA.

A contingent of researchers at the University of Rochester study the RNA of viruses to better understand how RNAs work and how they are involved in diseases. As COVID-19 continues to spread around the globe, RNA research provides an important foundation for developing antiviral drugs, vaccines, and other therapeutics to disrupt the virus and stop infections.

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Understanding RNA structure and function helps us understand how to throw a therapeutic wrench into what the COVID-19 RNA doesmake new virus that can infect more of our cells and also the cells of other human beings, says Lynne Maquat, professor of biochemistry and biophysics at the University of Rochester Medical Center and the director of Rochesters Center for RNA Biology.

In the past few decades, as scientists came to realize that genetic material is largely regulated by the RNA it encodes, that most of our DNA produces RNA, and that RNA is not only a target but also a tool for disease therapies, the RNA research world has exploded, Maquat says. The University of Rochester understood this.

In 2007, Maquat founded the Center for RNA Biology as a means of conducting interdisciplinary research in the function, structure, and processing of RNAs. The center involves researchers from both the River Campus and the Medical Center, combining expertise in biology, chemistry, engineering, neurology, and pharmacology.

While much of the research across the University has been put on pause, labs that are involved in coronavirus research remain active.

Our strength as a university is our diversity of research expertise, combined with our highly collaborative nature, says Dragony Fu, an assistant professor of biology on the River Campus and a member of the Center for RNA Biology. We are surrounded by outstanding researchers who enhance our understanding of RNA biology, and a medical center that provides a translational aspect where the knowledge gained from RNA biology can be applied for therapeutics.

In mammals, such as humans, DNA contains genetic instructions that are transcribedor copiedinto RNA. While DNA remains in the cells nucleus, RNA carries the copies of genetic information to the rest of the cell by way of various combinations of amino acids, which it delivers to ribosomes. The ribosomes link the amino acids together to form proteins that then carry out functions within the human body.

Many diseases occur when these gene expressions go awry.

COVID-19, short for coronavirus disease 2019, is caused by the novel coronavirus SARS-CoV-2. Like many other viruses, SARS-CoV-2 is an RNA virus. This means that, unlike in humans and other mammals, the genetic material for SARS-CoV-2 is encoded in RNA. The viral RNA is sneaky: its features cause the protein synthesis machinery of our cells to mistake it for RNA produced by our own DNA.

While SARS-CoV-2 is a new coronavirus, it likely replicates and functions similar to related coronaviruses that infect animals and humans, says Douglas Anderson, an assistant professor of medicine in the Aab Cardiovascular Research Institute and a member of the Center for RNA Biology, who studies how RNA mutations can give rise to human disease.

A graphic created by the New York Times illustrates how the coronavirus that causes COVID-19 enters the body through the nose, mouth, or eyes and attaches to our cells. Once the virus is inside our cells, it releases its RNA. Our hijacked cells serve as virus factories, reading the viruss RNA and making long viral proteins to compromise the immune system. The virus assembles new copies of itself and spreads to more parts of the body andby way of saliva, sweat, and other bodily fluidsto other humans.

Once the virus is in our cells, the entire process of infection and re-infection depends on the viral RNA, Maquat says.

Researchers Douglas Anderson, Dragony Fu, and Lynne Maquat are among the scientists at the University of Rochester who study the RNA of viruses to better understand how RNAs work and how they are involved in diseases. (University of Rochester photos / Matt Wittmeyer / J. Adam Fenster)

Maquat has been studying RNA since 1972 and was part of the earliest wave of scientists to realize the important role RNA plays in human health and disease.

Our cells have a number of ways to combat viruses in what can be viewed as an arms race between host and virus. One of the weapons in our cells arsenal is an RNA surveillance mechanism Maquat discovered called nonsense-mediated mRNA decay (NMD).

Nonsense-mediated mRNA decay protects us from many genetic mutations that could cause disease if NMD was not active to destroy the RNA harboring the mutation, she says.

Maquats discovery has contributed to the development of drug therapies for genetic disorders such as cystic fibrosis, and may be useful in developing treatments for coronavirus.

NMD also helps us combat viral infections, which is why many viruses either inhibit or evade NMD, she adds. The genome of the virus COVID-19 is a positive-sense, single-stranded RNA. It is well known that other positive-sense, single-stranded RNA viruses evade NMD by having RNA structures that prevent NMD from degrading viral RNAs.

Maquats lab is currently collaborating with a lab at Harvard University to test how viral proteins can inhibit the NMD machinery.

Like Maquat, Fu studies fundamental aspects of RNAand has found that his research on proteins may, too, be applicable to coronavirus research.

Fus lab analyzes enzymes and proteins that modify the chemical structure of RNA and how these chemical modifications impact the function of RNA. A research group at the University of California, San Francisco, recently identified an interaction between a protein made by the SARS-CoV-9 virus and a protein Fu studies.

This is an intriguing result, and we are currently thinking of ways this interaction could affect the host cell, Fu says. There is emerging evidence that RNA-based viruses undergo RNA modification, so we could use this knowledge to identify key links between the host and pathogen for development of a coronavirus vaccine or treatment.

One of the reasons viruses are such a challenge is that they change and mutate in response to drugs.

Targeting viral RNA, or the proteins it produces, is key for treating this disease.

That means novel virus treatments and vaccines have to be created each time a new strain of virus presents itself. Armed with innovative research on the fundamentals of RNA, scientists are better able to develop and test therapeutics that directly target the RNAs and processes critical to a viruss life cycle.

The University of Rochester Medical Center, for instance, is currently participating in a clinical trial to evaluate the safety and efficacy of a potential coronavirus treatment called remdesivir, an antiviral drug particularly tailored to attack RNA viruses. The drug inhibits RNA polymerase, an enzyme responsible for copying a DNA sequence into an RNA sequence.

Anderson has found that alternative therapeutics, such as the gene-editing technology CRISPR, may additionally usher in a new approach to how we target and combat infectious diseases, he says.

For the past few years, Andersons lab has developed tools and delivery systems that use the RNA-targeting CRISPR-Cas13 to treat human genetic diseases that affect muscle function. CRISPR-Cas13 is like a molecular pair of scissors that can target specific RNAs for degradation, using small, programmable guide RNAs.

When the health crisis first became apparent in Wuhan, China, researchers in Andersons lab turned their focus toward developing a CRISPR-Cas13 therapeutic aimed at SARS-CoV-2. Applying the knowledge already available about coronavirus RNA replication, they designed single CRISPR guide RNAs capable of targeting every viral RNA that is made within a SARS-CoV-2 infected cell. Using a novel cloning method developed in Andersons lab, multiple CRISPR guide-RNAs could be packaged into a single therapeutic vector (a genetically engineered carrier) to target numerous viral RNA sites simultaneously. The multi-pronged targeting strategy could be used as a therapy to safeguard against virus-induced cell toxicity and prevent escape of viruses which may have undergone mutation.

Infectious viruses and pandemics seemingly come out of nowhere, which has made it hard to rapidly develop and screen traditional small molecule therapeutics or vaccines, Anderson says. There is a clear need to develop alternative targeted therapeutics, such as CRISPR-Cas13, which have the ability to be rapidly reprogrammed to target new emerging pandemics.

While many new treatments for the novel coronavirus are being considered, there is one thing that is certain, Maquat says: Targeting viral RNA, or the proteins it produces, is key for treating this disease.

Tags: Arts and Sciences, Center for RNA Biology, COVID-19, Department of Biochemistry and Biophysics, Department of Biology, Douglas Anderson, Dragony Fu, featured-post, Lynne Maquat, medical center

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COVID-19: What's RNA research got to do with it? - University of Rochester