Potential drug target, inhibitor identified for SARS-CoV-2

Monday, 16 March, 2020

Potential drug target, inhibitor identified for SARS-CoV-2

Two new studies out of the US show promise for the treatment of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19).

The first study found that scientists have identified a potential drug target in a newly mapped protein of SARS-CoV-2. The structure was solved by a team including the University of Chicago, the Department of Energy’s Argonne National Laboratory, Northwestern University and the University of California, Riverside (UCR).

The SARS-CoV-2 protein Nsp15 is 89% identical to the Nsp15 protein from the earlier outbreak of SARS-CoV. Studies published in 2010 on SARS-CoV revealed that inhibition of Nsp15 can slow viral replication. This suggests drugs designed to target Nsp15 could be developed as effective drugs against COVID-19.

“The newly mapped protein, called Nsp15, is conserved among coronaviruses and is essential in their life cycle and virulence,” said Professor Andrzej Joachimiak, Co-Director of the Structural Biology Center at Argonne’s Advanced Photon Source (APS). “Initially, Nsp15 was thought to directly participate in viral replication, but more recently it was proposed to help the virus replicate possibly by interfering with the host’s immune response.”

Mapping a 3D protein structure of the virus, also called solving the structure, allows scientists to figure out how to interfere in the pathogen’s replication in human cells. The Nsp15 protein structure has now been released to the scientific community on the RSCB Protein Data Bank.

“The Nsp15 protein has been investigated in SARS as a novel target for new drug development, but that never went very far because the SARS epidemic went away, and all new drug development ended,” said Northwestern University’s Professor Karla Satchell, who leads the international team of scientists investigating the structure of SARS-CoV-2. “Some inhibitors were identified but never developed into drugs. The inhibitors that were developed for SARS now could be tested against this protein.”

Rapid upsurge and proliferation of SARS-CoV-2 raised questions about how this virus became so much more transmissible as compared to the SARS and MERS coronaviruses. The scientists are mapping proteins to address this issue.

“While the SARS-CoV-2 is very similar to the SARS virus that caused epidemics in 2003, new structures shed light on the small but potentially important differences between the two viruses that contribute to the different patterns in the spread and severity of the diseases they cause,” said UCR Professor Adam Godzik, whose team performed initial genome analysis and constructs design for protein synthesis.

Profs Satchell, Joachimiak and Godzik — along with their teams — will map the structure of some of the 28 proteins in the virus in order to see where drugs can throw a chemical monkey wrench into its machinery. The proteins are folded globular structures with precisely defined function and their ‘active sites’ can be targeted with chemical compounds.

The first step is to clone and express the genes of the virus proteins and grow them as protein crystals in miniature ice cube-like trays. Viewing these proteins down to the arrangement of their atoms requires an intense X-ray beam; thus, once the crystals are grown, the centre scientists will image them using the APS’s extremely bright light source in a process called X-ray crystallography.

Meanwhile, an international team of researchers has found that a protein produced by the human immune system can potentially inhibit several coronaviruses, including SARS-CoV-2. Their research, published in the journal bioRxiv, reveals that the LY6E protein impairs the coronavirus’s ability to initiate infection, which could lead to treatments for the illnesses caused by these viruses.

The story begins many years ago when Associate Professor Josh Schoggins, then a postdoctoral researcher in the lab of Dr Charles Rice at The Rockefeller University, was screening for antiviral genes and found that the LY6E gene unexpectedly enhanced the infectivity of the virus that causes flu. He continued this research on how LY6E enhanced flu infection after becoming a faculty member at The University of Texas Southwestern Medical Center (UT Southwestern); the project is now being led by Dr Katrina Mar, a postdoctoral researcher in his laboratory.

In 2017, Dr Stephanie Pfaender — a postdoctoral researcher from the lab of Swiss coronavirus expert Dr Volker Thiel — visited the Rice lab to use Assoc Prof Schoggins’ screening technology to find genes that inhibit coronavirus. This led to the discovery that LY6E potently inhibited coronavirus.

“When we later learned that LY6E did the opposite with coronavirus — that is, it inhibited rather than enhanced infection — we were immediately intrigued, particularly because we had already developed an animal model to study the role of LY6E during viral infection,” Assoc Prof Schoggins said. Thus, the Thiel and Rice labs began to further study the LY6E protein.

The team had worked for almost two years on its study before the current coronavirus outbreak. They had found that the LY6E protein inhibited other coronaviruses — the ones implicated in SARS and MERS — when the pathogen that causes COVID-19 came to the world’s attention in January, Assoc Prof Schoggins said.

In primate kidney cells, which are frequently used as models in coronavirus research, the researchers had determined that LY6E impairs the ability of the virus to fuse with host cells. If the virus is unable to fuse with those cells, it cannot initiate infection. Dr Thiel was able to get a sample of human COVID-19 from the current outbreak and spearheaded efforts to determine if LY6E also inhibited fusion of the COVID-19 virus, finding that it does.

Meanwhile, experiments conducted by Dr Mar on the UT Southwestern mouse model exposed to murine coronavirus showed that Ly6e (the mouse version of the gene) is critical for protecting immune cells from infection. In the absence of Ly6e, immune cells — such as dendritic cells and B cells — become more susceptible to infection and their numbers drastically decrease. This makes it harder for the immune system to fight off the infection, which worsens the disease, Assoc Prof Schoggins said.

“Remarkably, this potent inhibitory effect carried over to all the coronaviruses we tested, including those responsible for the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak in 2003, the Middle East respiratory syndrome (MERS) coronavirus in 2012 and the recently emerged causative agent of COVID-19, known as SARS-CoV-2,” Assoc Prof Schoggins said.

He stressed, however, that the mouse coronavirus used in that experiment is very different from the coronavirus in the current outbreak. Rather than being a respiratory illness, the mouse coronavirus they studied infects the liver, causing hepatitis. The mouse coronavirus is also usually not lethal — but for mice lacking Ly6e, it was deadly.

“In spite of those differences, it’s widely accepted as a model for understanding basic concepts of coronavirus replication and immune responses in a living animal,” Assoc Prof Schoggins said. “Our study brings new insight into how critical these antiviral genes are for controlling viral infection and mounting proper immune responses against the virus. Because LY6E is a naturally occurring protein in humans, we hope this knowledge may help in the development of therapies that might one day be used to treat coronavirus infections.”

The researchers concluded that antiviral fusion inhibitors have been successfully implemented for HIV-1 and that a therapeutic approach mimicking the mechanism of action of LY6E could provide a first line of defence against novel coronavirus infections.

Image caption: This newly mapped coronavirus protein, called Nsp15, helps the virus replicate.

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