​Nat Commun and Yin Hang's group report that switchable TLR activation/inhibitors provide new strategies for precise immune regulation

Editor | Enzyme immunosuppressive agents are widely used in autoimmune diseases and suppress rejection of organ transplants
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However, immunosuppressants can also suppress normal immunity, so long-term use or improper use can cause serious adverse reactions
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The immunosuppressant Humira (Figure 1), which is widely used clinically and is called the "King of Medicine" (Figure 1), also has problems such as reduced immunity and susceptibility to infection during the medication period
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Figure 1.
Immunosuppressive drug Humile On July 16, 2021, Yin Hang's group from the School of Pharmacy of Tsinghua University published an article titled Tetrasubstituted Imidazoles as Incognito Toll-like Receptor 8 A(nta)gonists in Nature Communications
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Professor Yin Hang’s research group has long focused on the study of innate immune receptor mechanisms.
Recently, it has developed an innovative small molecule CU-CPD107 that targets TLR8.
Through the exploration of the molecular mechanism, it has found that many previous immune suppression solutions have been solved.
A new strategy for drug abuse
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This molecule has an inhibitory effect on the immune signal caused by the TLR8 small molecule activator, but only when ssRNA and other virus-related molecular patterns exist, it can be converted into a TLR8 activator to specifically enhance the immune response
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This study conducted an in-depth study on the inhibition/activation effect of CU-CPD107 two-way type, respectively, and provided a new idea for the development of antiviral drugs
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In response to the current pandemic of the new coronavirus, novel antiviral treatments are urgently needed
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TLR8 is an important member of the Toll-like receptor family, which can recognize viral ssRNA (such as SARS-CoV-2) and plays an important role in antiviral immunity
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However, classic TLR8 modulators (such as R848) can cause non-specific systemic inflammatory reactions, which are greatly restricted in the process of clinical application.
Therefore, new strategies are needed to more accurately regulate the activity of TLR8
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In this study, a series of new small molecules were rationally designed.
These small molecules have a tetra-substituted imidazole skeleton and can specifically target TLR8
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As the lead compound, CU-CPD107 can effectively inhibit the TLR8 signal induced by small molecule agonists such as R848
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More interestingly, in the presence of viral ssRNA, CU-CPD107 showed unexpected and unique synergistic activation activity (Figure 2)
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At the same time, the study also deeply explored the bidirectional characteristic mechanism of this activation/inhibition
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The TLR8/CU-CPD107 co-crystal structure shows that CU-CPD107 inhibits the binding of activators such as R848 to TLR8 by locking the TLR8 dimer in its resting state, thereby exhibiting an inhibitory effect
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Through molecular docking and site-directed mutagenesis, the cooperative activation mechanism of CU-CPD107 on TLR8 is similar to that of uridine, and its combination enhances the activation of TLR8 induced by ssRNA
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The discovery of CU-CPD107 provides new ideas for the design of new immune activators and the development of antiviral drugs
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Figure 2.
Model diagram of the mechanism of action of TLR8's new small molecule CU-CPD107
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Since the outbreak of the new coronavirus, Hang Yin's research team has been racing against time to actively carry out research related to the new crown.
From basic scientific research to application transformation, a series of research results have been continuously obtained
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On January 2, 2021, the research team reported in Cell Discovery the research results titled SARS-CoV-2 nucleocapsid protein undergoes liquid-liquid phase separation into stress granules through its N-terminal intrinsically disordered region, which revealed the new coronavirus The molecular mechanism of phase separation provides new targets and strategies for the development of drugs targeting proteins in host cells
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Although a variety of anti-coronavirus vaccines are currently on the market, there is still an urgent need for small molecule-oriented drug research and development.
This study reveals a new mechanism of antiviral immunity and solves many problems with previous immunomodulators.
It is also congenital.
The precise regulation of the immune response provides a new strategy
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At the same time, Professor Yin Hang’s research team worked closely with researcher Deng Fei of Wuhan Institute of Virology to carry out the research and development of innovative new coronavirus drugs based on innate immunity.
The new TLR8 small molecule regulator CU-CPD107 was developed to prevent the invasion of live new coronaviruses.
It has strong antiviral activity in the process of infecting cells, laying the foundation for further research and development of anti-coronavirus drugs
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In addition, it has established a long-term cooperative relationship with Toshiyuki Shimizu, an advanced structural biologist in the field, at the University of Tokyo, Japan.
Lead compounds obtained from high-throughput screening are co-crystallized with specific TLR targets, and structure-based optimization and The structure-activity relationship studies have formed complementarity, further revealing the molecular mechanism of small molecule ligand/receptor binding
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The results of cooperation in recent years have also been published in many journals such as Nature Chemical Biology, Cell Chemical Biology, Journal of Medicinal Chemistry, and revealed new mechanisms of innate immunity and anti-virus
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