Cell Res: Confused with the new coronavirus, Westlake University/Fudan University has teamed up to design a new corona protein inhibitor

The new crown outbreak that is ravaging the world is a common test for all mankind.
the outbreak, scientists have been working to understand the virus invasion, research the way to crack.
vaccine and antibodies as an important means of preventing and treating neo-coronary pneumonia, and much progress has been made.
is there any other way to effectively contain the new coronavirus than these tools? Recently, the Westlake University Party Bobo Team, Zhou Qiang Team and Fudan University School of Basic Medicine Land Team jointly published a research paper entitled: Engineered Trimeric ACE2 Binds Viral Spike and protein locks it in "Three-up" Conformation to Potently inhibit SARS-CoV-2 infect.
research team based on the design and transformation of the new coronavirus subject ACE2, built a variety of ACE2 triglomer proteins, of which T-ACE2 and the new coronavirus pyrethroid protein affinity reached KD-lt;1 pM, while greatly improving the virus inhibition activity.
, the team created an ACE2 prosthesis protein that "confused" the virus and was more than 1,000 times more "attractive" to the virus than ACE2 itself.
previous study of the artificial design of the ACE2 prosthesis protein "attractive" virus found that the key to the new coronavirus infects human cells is the binding of the coronavirus's prick protein with the human ACE2 protein.
, it was the hedgehog protein that "hijacked" ACE2, which originally controlled blood pressure, and invaded the body by binding to it.
Since the ACE2 protein is the gate for the virus to invade the human body, after the new coronavirus enters the human body, if we have an ACE2 prosthesis protein, "confused" the virus, can we achieve the effect of suppressing the virus? Based on this idea, Dr. Party Bobo, who has been engaged in protein design and transformation for a long time, thought of constructing an artificial ACE2 prosthesis protein to bind the virus, thus achieving the goal of denying the virus entry into the human body.
Recent studies have shown that the new coronavirus hedgehog protein exists in the form of a trimer, so the researchers envision whether it is possible to build an ACE2 triglomer protein and hedgehog protein trimer to achieve 3 to 3 or at least 2 to 2 binding? Subsequently, the researchers delved into the structure of the coronavirus prickly protein and made a series of design modification attempts, they obtained a triumvirus protein T-ACE2, which can be associated with the new coronavirus hedgehog protein affinity to KD-lt;1 pM, compared to the original ACE2 monomer, with the hedgehog protein affinity increased by more than 1000 times.
affinity is high, the virus will give priority to T-ACE2, thereby losing the ability to bind to cell surface ACE2, so T-ACE2 has a very strong viral inhibition activity.
Although the hedgehog protein itself exists in the form of a trinity, in the absence of a bind, the three monomer structures in the trimer are different, and at most only one monomer in the trimer is in an open structure to bind to the subject.
increase in T-ACE2 and prickly protein affinity suggests that T-ACE2 may induce changes in the prickly protein composition.
to further reveal how T-ACE2 binds to prickly proteins, the team analyzed the electroscopic structure of T-ACE2 and the new coronavirus hedgehog protein complex.
structure shows that T-ACE2 can indeed induce significant structural changes in the new coronary prickly protein, with three monoglobins in an open state at the same time and binding to three ACE2s at the same time.
"At the beginning of the design, we were completely unsure whether the ACE2 tripolymer would have an effect, but the more amazing thing is that the affinity really improved greatly after T-ACE2, and in the process of binding the hedgehog protein, the real induced hedgehog protein has undergone structural changes, so that it can be firmly binding the hedgehog protein."
did this change happen? It is not clear, but this should have important revelations for understanding the interaction between the hedgehog protein and the subject protein ACE2.
the unexpected T-ACE2-induced changes in the structure of the hedgehog protein, which I found most interesting.
"T-ACE2 and the structure of the new coronary protrusion protein complex T-ACE2 or can adapt to more new coronary similar viruses with the development of the epidemic normalization, the accumulation of virus mutations, the existing protein inhibitors (such as antibodies) for the new coronavirus and its potential mutations are facing a test.
the development of inhibitors that can suppress the new coronavirus and its mutant strains on a broad spectrum will become an effective means to deal with the variation of the new coronavirus and the normalization of the epidemic.
During the design and modification of ACE2 trimer proteins, in order to maximize the broad-spectrum applicability of modified proteins to viruses and their mutant strains, the researchers chose to retain the natural ACE2 sequence completely (1-615) because the modification based on the natural ACE2 sequence can be adapted to a variety of mutant viruses.
In this study, the researchers also confirmed that T-ACE2 has strong inhibition activity against new coronavirus, eight different natural new crown strains, SARS virus and two new corona-like viruses, with an IC50 value in the range of 0.1nM-3nM.
new coronavirus infects human cells through the subject protein ACE2, so inhibitors based on the subject protein ACE2 have a broader spectrum of inhibition than antibodies to new coronavirus mutant strains.
addition, such proteins, designed and modified based on the subject ACE2, will most likely be used to suppress new or reproduced new corona-like viruses.
the clinical application of T-ACE2 as a viral inhibitor protein has yet to be further tested.
Party Bobo said that T-ACE2 because of the virus prickly protein has a very strong affinity, is expected to be used in the development of virus detection methods, but also because T-ACE2 is completely based on the natural ACE2 sequence design, so the broad-spectrum applicability of the new crown-like virus will be relatively high, such T-ACE2-based detection methods will also be widely used in the new corona-like virus detection.
West Lake University Special Researcher Party Bobo, Zhou Qiang, Fudan University land as the paper's correspondent, West Lake University Guo Liang, Bi Jingjing, Yan Renhong, Zhang Wei, Fudan University Wang Xinling, Xu Wei as the co-first author of this paper.