“No frowns this time, and we took the initiative to respond quickly.” Rao Zihe, member of the Standing Committee of the 13th National Committee of the Chinese People’s Political Consultative Conference, chairman of the Tianjin Science and Technology Association, and academician of the Chinese Academy of Sciences When looking for him to study the structure of SARS virus protein (main protease), his first reaction was frowning. This time, Rao Zihe’s “foundation” comes from the team has been “struggling” with the virus for 17 years. The accumulation of scientific research for many years has given him a chance to compete with the new crown virus.

Since January this year, the emergency scientific research team led by him has successfully analyzed two important targets of new coronaviruses-the main protease and RNA dependent RNA polymerization The three-dimensional structural information of the enzyme has laid an important foundation for the development of drugs against new coronary pneumonia. These two studies were published in March in the international authoritative journals “Nature” and “Science”.


17 years of sharpening a sword and a viral “hard bar”

When the SARS outbreak broke out in 2003, Rao Zi and Danger were ordered to overcome various difficulties, Formed a combative “SARS research group”, in only three months in the world to analyze the three-dimensional spatial structure of the first SARS virus protein (main protease), provides a key structural basis for the development of anti-SARS drugs.

Since then, Rao Zihe and his team at the Chinese Academy of Sciences, Tsinghua University, Nankai University, and Shanghai University of Science and Technology have been on the “hard bar” of the coronavirus. In early January of this year, when the new corona virus appeared, Rao Zihe keenly caught the familiar “smell” and took the initiative to start the first round of competition with the new corona virus.

Within a week of receiving the new coronavirus sample, Rao Zi and // Yang Haitao ’s research team has determined to express the new coronavirus 3CL hydrolase (Mpro) which is the main protease High resolution crystal structure.

“The main protease is like a skilled tailor, through its ‘magic shears’, the two super-long replicase polypeptides necessary for the propagation and replication of the new coronavirus ( pp1a and pp1ab) precisely “cut” into multiple parts (such as RNA-dependent RNA polymerase, helicase, etc.), and then further assembled into a huge copy transcription machine to start the virus replication. Say, “The main protease of the SARS virus has been” cracked “by us before, and we have not stopped the research on coronavirus since SARS, so this time we can quickly see the new crown virusIts true face. ”

When the nationwide epidemic started, the team of academicians Rao Zihe and the academicians had already won the battle. On the eve of the Spring Festival, the team first announced the main protease of the new coronavirus worldwide The precise three-dimensional structure information, and real-time sharing with domestic and foreign counterparts.


Decrypt the virus to point the way for new drug development

“Anti-new coronavirus has three important drug targets, one is the main protease, which we have cracked. The ‘RdRp (RNA-dependent RNA polymerase) -nsp7-nsp8 complex’ in the other two targets is another key core of the coronavirus replication / transcription mechanism. “Rao Zihe introduced that the new coronavirus invades cells , Began to copy and clone a lot. RNA polymerase, as the core component of the replication machine, is the key for the virus to reproduce in large quantities, so it is one of the most important antiviral drug targets. Disrupting the function of the core device can prevent the virus from spreading and spreading, and achieve the ultimate therapeutic purpose.

“Radexivir was considered to be a promising clinical drug in the treatment of new coronary pneumonia at that time. However, because the three-dimensional structure of RdRp is completely unknown, Redisi The mechanism of how Wei accurately targets RdRp is unclear, which has set obstacles for further development of more effective antiviral drugs.

“No one had cracked it before, and when we studied the SARS virus, we could not crack its RdRp, so analyzing the three-dimensional structure of the new coronavirus RdRp is one of our most important “The goal.” Rao Zihe introduced that they cracked the three-dimensional structure of RdRp by cryo-electron microscopy. Although the team’s technical level was high, it was still very difficult to make the expressed protein complex. “You can only rely on repeated experiments. If you fail, you can continue. There are no shortcuts.”

The Chinese New Year only stayed at home for one day. Return to the laboratory in Shanghai. “When analyzing the main protease, I can still sleep peacefully. When I study the target of RdRp, I really have insomnia for many days. Every day I think of RdRp.” Rao Zihe said that the entire team is also overnight to solve this problem as soon as possible. Carry out experiments, and often hold joint research meetings, repeated discussions.

Speaking of Rao Zi and the degree of anxiety at that time, the team members later joked that Teacher Rao was so anxious that even the flies in the laboratory “swear” all over.

After hundreds of experiments, Rao Zi and the academician team took the lead in successfully analysing the three-dimensional spatial structure of the new coronavirus RdRp near atomic resolution internationally, revealing the transcription and replication of the genetic material of the virus The structural characteristics of the core engine of the machine.

To see the structure of the virus clearly, in order to find the “crack technique”, the research results of the team of Rao Zihe and the academician have opened up the development of special drugs against new coronary pneumonia New way. Rao Zihe said that the coordinates of the structure are shared with the whole world, and he hopes to cooperate with domestic and international scientific researchers to develop special drugs for new coronary pneumonia as soon as possible and overcome this common “enemy” as soon as possible.

(Original title Rao Zihe: Actively attack and crack virus drug targets)