Coronavirus structure reveals drug targets

Coronaviruses are types of viruses that typically affect the respiratory tracts of birds and mammals, including humans. Doctors associate them with the common cold, bronchitis, pneumonia, and severe acute respiratory syndrome (SARS), and they can also affect the gut.

These viruses are typically responsible for common colds more than serious diseases. However, coronaviruses are also behind some more severe outbreaks.

Most recently, authorities identified a new coronavirus outbreak in China that has now reached other countries. It has the name coronavirus disease 2019, or COVID-19.

What is a coronavirus?

Two human coronaviruses are responsible for a large proportion of common colds: OC43 and 229E.

The name “coronavirus” comes from the crown-like projections on their surfaces. “Corona” in Latin means “halo” or “crown.”

Among humans, coronavirus infections most often occur during the winter months and early spring. People regularly become ill with cold due to a coronavirus and may catch the same one about 4 months later.

This is because coronavirus antibodies do not last for a long time. Also, the antibodies for one strain of coronavirus may be ineffective against another one.

Types

Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae.

Different types of human coronaviruses vary in how severe the resulting disease becomes, and how far they can spread.

Doctors currently recognize seven types of coronavirus that can infect humans.

Common types include:

(a) 229E (alpha coronavirus)
(b) NL63 (alpha coronavirus)
(c) OC43 (beta coronavirus)
(d) HKU1 (beta coronavirus)
Rarer strains that cause more severe complications include MERS-CoV, which causes Middle East respiratory syndrome (MERS), and SARS-CoV, the virus responsible for severe acute respiratory syndrome (SARS).

In 2019, a dangerous new strain called SARS-CoV-2 started circulating, causing the disease COVID-19.

Structure of coronavirus

1. In a newly mapped protein of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), a potential drug target has been identified. The structure was solved by a team including the University of Chicago (U of C), the U.S. Department of Energy’s (DOE) Argonne National Laboratory, Northwestern University Feinberg School of Medicine and the University of California, Riverside School of Medicine (UCR).

According to scientists’s findings drugs that had previously been in development to treat the earlier SARS outbreak could now be developed as effective drugs against COVID-19.

The protein Nsp15 from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is 89% identical to the 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 lifecycle and virulence. 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,” said Joachimiak.

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.

Satchell said, “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. 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 could became so much more transmissible as compared to the SARS and MERS coronaviruses. The scientists are mapping the 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,” Godzik said.

Northwestern is the lead site for the international center that comprises eight institutions, including U of C and UCR. The center has committed resources across all eight sites since the news of the new coronavirus was made public in January. The structure of Nsp15 is the first structure solved by the center.

2. Like other coronaviruses, SARS-CoV-2 particles are spherical and have proteins called spikes protruding from their surface. These spikes latch onto human cells, then undergo a structural change that allows the viral membrane to fuse with the cell membrane. The viral genes can then enter the host cell to be copied, producing more viruses. Recent work shows that, like the virus that caused the 2002 SARS outbreak, SARS-CoV-2 spikes bind to receptors on the human cell surface called angiotensin-converting enzyme 2 (ACE2).

To help support rapid research advances, the genome sequence of the new coronavirus was released to the public by scientists in China. A collaborative team including scientists from Dr. Jason McLellan’s lab at the University of Texas at Austin and the NIAID Vaccine Research Center (VRC) isolated a piece of the genome predicted to encode for its spike protein based on sequences of related coronaviruses. The team then used cultured cells to produce large quantities of the protein for analysis.

The researchers used a technique called cryo-electron microscopy to take detailed pictures of the structure of the spike protein. This involves freezing virus particles and firing a stream of high-energy electrons through the sample to create tens of thousands of images. These images are then combined to yield a detailed 3D view of the virus.

The researchers found that the SARS-CoV-2 spike was 10 to 20 times more likely to bind ACE2 on human cells than the spike from the SARS virus from 2002. This may enable SARS-CoV-2 to spread more easily from person to person than the earlier virus.

Despite similarities in sequence and structure between the spikes of the two viruses, three different antibodies against the 2002 SARS virus could not successfully bind to the SARS-CoV-2 spike protein. This suggests that potential vaccine and antibody-based treatment strategies will need to be unique to the new virus.

“We hope these findings will aid in the design of candidate vaccines and the development of treatments for COVID-19,” says Dr. Barney Graham, VRC Deputy Director.

The researchers are currently working on vaccine candidates targeting the SARS-CoV-2 spike protein. They also hope to use the spike protein to isolate antibodies from people who have recovered from infection by the new coronavirus. If produced in large quantities, such antibodies could potentially be used to treat new infections before a vaccine is available. In addition, NIH researchers are pursuing other approaches to treating the virus.