Two “Natures” on the same day reveal why new coronavirus infections are stronger

In the second quarter of 2020, the COVID-19 outbreak caused by the new coronavirus (SARS-CoV-2) is still spreading around the world, with nearly 800,000 confirmed cases and the number of people infected still increasing. It has to be said that the new virus is very cunning, and our knowledge of its infection characteristics is still limited.

With the efforts of two research teams at Tsinghua University and the University of Minnesota, two new studies have been published online in the leading academic journal Nature, and scientists have begun to explain why the virus is more contagious than the SARS virus, starting with its unique structure.

The two papers, in the form of “accelerated review articles”, provide important guidance for researchers to understand the propagation characteristics of COVID-19 as soon as possible and how to develop vaccines and drugs.

We now know that when the new coronary virus invades human cells, the S protein on its surface plays a key role. The S protein is combined with receptor ACE2 on human cells through the receptor domain (RBD), which is the first step in initiating infection and an important target for neutralizing antibody and vaccine development.

In the joint research work of Professor Wang Xinquan and Zhang Linxuan of Tsinghua University, the researchers successfully obtained the composite crystals combined with the new coronavirus RBD and human ACE2, and obtained high-resolution crystal structure data using X-ray diffraction technology. It is possible to see clearly how the new coronavirus RBD interacts with the receptor at the atomic level.

The researchers pinpointed the amino acid sites where the new coronavirus RBD interacted directly with ACE2 and found that the pattern of the combination of ACE2 and THE SARS virus was very similar, combined with the same ACE2 amino acid residue, and that there was only a few differences in amino acid residues on RBD. These small differences, but can make the new coronavirus binding receptor solder ability to become more powerful.

The new coronavirus RBD and SARS virus RBD were compared with the parts of the receptor’s direct interaction, with most of the key sites marked with black and red dots being the same or similar (Photo Source: Resources 1)

However, the paper points out that the higher binding force to the receptor is only one reason why the new coronavirus is more powerful. Areas other than the S protein RBD, such as special enzyme cutting sites, are also important factors in the rapid spread of the new coronavirus.

Prior to the paper’s peer review, the team shared their results in the first place through bioRxiv, a preprinted platform, and its main conclusions were supported by other studies.

Another paper, which was also launched in Nature, was led by Professor Li Li of the University of Minnesota. The researchers also determined the three-dimensional structure of the compound that binds the new coronavirus RBD to the human receptor ACE2, based on X-ray diffraction data, with a resolution of 2.68 inches.

Compared with the amino acid sequence of sars virus, the researchers identified two structural characteristics of the new coronavirus with stronger binding force from the receptor. On the one hand, the new coronavirus is close to the receptor with a more compact structure and more contact with the receptor.

What is more noteworthy is that from past experience, there are two important “virus-binding hotspots” on the contact surface of SARS virus interaction with ACE2. Looking at the new coronavirus, they found that the virus binds to several amino acids near the hot spot, and these changes make the virus bind to the receptor more stable, thus giving the new coronavirus a stronger receptor binding affinity.

On the contact surface of the virus RBD-receptor, the amino acids near the virus bind to the hot spot have small but important differences (Photo: Resources 2)

The researchers also demonstrated experimentally that RaTG13, a bat coronavirus that is more similar to the new coronavirus in the sequence, can also bind directly to human ACE2 receptors. This result supports the idea that the new coronavirus is being transmitted from animaltos to humans.

As scientists gain a deeper and clearer understanding of how the new coronavirus binds to human cell receptors, this structural information could help researchers find and design drugs to block viral infections. “If a new antibody drug can bind to these receptor binding sites of the new coronavirus and bind faster and stronger than the receptor, then the antibody drug can keep the virus out of the cell and hopefully act as an effective anti-infection therapy.” Professor Li said.