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RNAi is a highly conserved post-transcriptional gene silencing mechanism in eukaryotes, and it is also a highly effective antiviral natural immune mechanism
.
When the virus infects the host cell, the dsRNA produced by viral RNA replication is recognized by Dicer, a key protein in the RNAi pathway, and cut into virus-derived small interfering RNA (vsiRNA).
These vsiRNAs are further assembled into the RNA-induced silencing complex RISC to mediate Degradation of viral RNA in infected cells
.
At the same time, many viruses antagonize RNAi antiviral immunity by encoding viral RNAi suppressors (Viral Suppressor of RNAi, VSR)
.
In 2017, the team of Zhou Xi, a researcher at the Wuhan Institute of Virology, Chinese Academy of Sciences/State Key Laboratory of Virology, found that the non-structural protein 3A of enterovirus EV71 has RNAi suppression (VSR) activity, which can prevent Dicer from cutting viral dsRNA and producing vsiRNA ; And the EV71 mutant virus lacking 3A-VSR activity can produce a large number of vsiRNA in the infected mammalian cells and in vivo, which stimulates the RNAi antiviral response, thus proving that RNAi as an antiviral immunity still exists in mammals, and reveals A mechanism for human viruses to escape RNAi immunity [Immunity ("Immunity") 2017]
.
In addition, the team also discovered VSR proteins encoded by various important human viruses such as flavivirus (dengue virus, Japanese encephalitis virus, Zika virus, etc.
), SARS-CoV-2, alpha virus, rubella virus, hepatitis C virus, etc.
, and Reveal the molecular mechanism of its interaction with the host RNAi antiviral pathway (Cell Research 2019, Science Advances 2020, Journal of Virology 2020, SCIENCE CHINA Life Sciences 2020, Virologica Sinica 2020, Viruses 2021)
.
The scientific research team innovatively proposed a drug development concept that targets VSR to release the antiviral potential of RNAi
.
The study took the enterovirus EV71 as the object, and designed several VSR-targeting peptides (VTP) for the key functional regions of the VSR of its 3A protein
.
These VTPs can directly bind to the 3A protein, and through competition, the 3A inhibits RNAi in EV71-infected cells, and induces the production of a large number of viral vsiRNAs; these vsiRNAs are then assembled into RISC to mediate EV71 RNA in the infected cells.
Degradation, effectively inhibit EV71 replication
.
VTP can also release RNAi antiviral response in mice, produce a large amount of vsiRNA, inhibit the replication of EV71 in various organs of mice, and save mice death and clinical symptoms caused by virus infection
.
At the same time, the target region on the 3A protein targeted by VTP is highly conserved among the 3A proteins of a variety of enteroviruses.
Studies have also found that VTP can inhibit the replication of a variety of enteroviruses and has broad-spectrum anti-enterovirus activity
.
This study confirmed for the first time that VTP-specific targeting of VSR can effectively release RNAi antiviral immunity in virus-infected cells and in vivo, fully demonstrating the physiological and functional importance of RNAi as mammalian antiviral immunity
.
From the perspective of antiviral drug development, the study found that VSR is a new class of drug targets based on a new antiviral mechanism, and developed a first-in-class candidate antiviral drug against enterovirus VSR.
The development of antiviral drugs for important viruses provides new ideas and strategies
.
In addition, VTP for enterovirus has lower toxicity and antigenicity in animals, higher thermal stability and protease stability, and is expected to be further developed as a new type of medicine for the treatment of enterovirus infections such as hand, foot and mouth
.
On September 22, related research results were published online on Immunity titled Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo
.
Wuhan Institute of Virology/State Key Laboratory of Virology and Fudan University Ministry of Education of Medical Molecular Virology/Key Laboratory of Health and Health Commission completed this research in cooperation
.
The research has applied for PCT and invention patents in many countries
.
Wuhan Institute of Virology and others revealed new strategies for the development of antiviral drugs targeting viral RNAi inhibitors.
Source: Wuhan Institute of Virology, Chinese Academy of Sciences
.
When the virus infects the host cell, the dsRNA produced by viral RNA replication is recognized by Dicer, a key protein in the RNAi pathway, and cut into virus-derived small interfering RNA (vsiRNA).
These vsiRNAs are further assembled into the RNA-induced silencing complex RISC to mediate Degradation of viral RNA in infected cells
.
At the same time, many viruses antagonize RNAi antiviral immunity by encoding viral RNAi suppressors (Viral Suppressor of RNAi, VSR)
.
In 2017, the team of Zhou Xi, a researcher at the Wuhan Institute of Virology, Chinese Academy of Sciences/State Key Laboratory of Virology, found that the non-structural protein 3A of enterovirus EV71 has RNAi suppression (VSR) activity, which can prevent Dicer from cutting viral dsRNA and producing vsiRNA ; And the EV71 mutant virus lacking 3A-VSR activity can produce a large number of vsiRNA in the infected mammalian cells and in vivo, which stimulates the RNAi antiviral response, thus proving that RNAi as an antiviral immunity still exists in mammals, and reveals A mechanism for human viruses to escape RNAi immunity [Immunity ("Immunity") 2017]
.
In addition, the team also discovered VSR proteins encoded by various important human viruses such as flavivirus (dengue virus, Japanese encephalitis virus, Zika virus, etc.
), SARS-CoV-2, alpha virus, rubella virus, hepatitis C virus, etc.
, and Reveal the molecular mechanism of its interaction with the host RNAi antiviral pathway (Cell Research 2019, Science Advances 2020, Journal of Virology 2020, SCIENCE CHINA Life Sciences 2020, Virologica Sinica 2020, Viruses 2021)
.
The scientific research team innovatively proposed a drug development concept that targets VSR to release the antiviral potential of RNAi
.
The study took the enterovirus EV71 as the object, and designed several VSR-targeting peptides (VTP) for the key functional regions of the VSR of its 3A protein
.
These VTPs can directly bind to the 3A protein, and through competition, the 3A inhibits RNAi in EV71-infected cells, and induces the production of a large number of viral vsiRNAs; these vsiRNAs are then assembled into RISC to mediate EV71 RNA in the infected cells.
Degradation, effectively inhibit EV71 replication
.
VTP can also release RNAi antiviral response in mice, produce a large amount of vsiRNA, inhibit the replication of EV71 in various organs of mice, and save mice death and clinical symptoms caused by virus infection
.
At the same time, the target region on the 3A protein targeted by VTP is highly conserved among the 3A proteins of a variety of enteroviruses.
Studies have also found that VTP can inhibit the replication of a variety of enteroviruses and has broad-spectrum anti-enterovirus activity
.
This study confirmed for the first time that VTP-specific targeting of VSR can effectively release RNAi antiviral immunity in virus-infected cells and in vivo, fully demonstrating the physiological and functional importance of RNAi as mammalian antiviral immunity
.
From the perspective of antiviral drug development, the study found that VSR is a new class of drug targets based on a new antiviral mechanism, and developed a first-in-class candidate antiviral drug against enterovirus VSR.
The development of antiviral drugs for important viruses provides new ideas and strategies
.
In addition, VTP for enterovirus has lower toxicity and antigenicity in animals, higher thermal stability and protease stability, and is expected to be further developed as a new type of medicine for the treatment of enterovirus infections such as hand, foot and mouth
.
On September 22, related research results were published online on Immunity titled Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo
.
Wuhan Institute of Virology/State Key Laboratory of Virology and Fudan University Ministry of Education of Medical Molecular Virology/Key Laboratory of Health and Health Commission completed this research in cooperation
.
The research has applied for PCT and invention patents in many countries
.
Wuhan Institute of Virology and others revealed new strategies for the development of antiviral drugs targeting viral RNAi inhibitors.
Source: Wuhan Institute of Virology, Chinese Academy of Sciences
