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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature RNA interference (RNAi) is the main antiviral mechanism in plants and invertebrates, but the lack of detectable viral (v) siRNAs in mammalian cells after viral infection questioned the functional relevance of this pathway in mammalian immunity
.
On September 22, 2021, the Zhou Xi team of Wuhan Institute of Virology of Chinese Academy of Sciences/State Key Laboratory of Virology and the land team of the Ministry of Education of Medical Molecular Virology of Fudan University/Key Laboratory of Health and Health Commission of Fudan University jointly published an online research titled “Inhibition of Viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo" research paper, the research designed a series of specifically targeting enterovirus A71 (EV-A71) encoded protein 3A, an RNAi (VSR) virus suppressor Of peptides
.
These peptides abolished the VSR function of EV-A71 in infected cells, and resulted in the accumulation of vsiRNA and the reduction of virus replication
.
These vsiRNAs are functional, as evidenced by RISC loading and silencing of target RNA
.
The effect of VSR targeting peptide (VTP) on EV-A71 and another enterovirus Coxsackie virus-A16 infection was ablated after removing Dicer1 or AGO2, the core component of the RNAi pathway
.
In vivo, VTP treatment protects mice from the lethal EV-A71 attack through detectable vsiRNA
.
The results of this study provide evidence for the functional relevance of RNAi in mammalian immunity and propose treatment strategies for infectious diseases
.
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 host cells, 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 Zhouxi team’s collaborative study found that the non-structural protein 3A of enterovirus EV71 has RNAi suppression (VSR) activity, which can prevent Dicer from cutting the viral dsRNA and producing vsiRNA; and the EV71 mutant virus lacking 3A-VSR activity It can produce a large number of vsiRNAs in the infected mammalian cells and the body to stimulate RNAi antiviral response, thus proving that RNAi as an antiviral immunity still exists in mammals, and revealing a mechanism by which human viruses escape RNAi immunity (Immunity 2017)
.
In addition, they also discovered VSR proteins encoded by many 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 revealed The molecular mechanism of its interaction with the host RNAi antiviral pathway (Cell Res.
2019, Sci Adv.
2020, J Virol.
2020, Sci China-Life Sci.
2020, Virol Sin.
2020, Viruses 2021)
.
In this study, the research team innovatively proposed a drug development concept that targets VSR to release the antiviral potential of RNAi
.
They 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
.
More importantly, 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.
The research team also found that VTP can inhibit the replication of a variety of enteroviruses and has broad-spectrum anti-intestinal virus 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, which fully proves the physiological and functional importance of RNAi as mammalian antiviral immunity
.
More importantly, from the perspective of antiviral drug development, the research is based on a new antiviral mechanism and found that VSR is a new type of drug target, and developed a first-in-class candidate for the enterovirus VSR mechanism.
Antiviral drugs provide new ideas and strategies for the development of antiviral drugs for other important viruses
.
In addition, VTP for enteroviruses has very low toxicity and antigenicity in animals, high 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
.
At the same time, the research has applied for invention patents in China, PCT, the United States, Japan, and Australia
.
Article link: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature RNA interference (RNAi) is the main antiviral mechanism in plants and invertebrates, but the lack of detectable viral (v) siRNAs in mammalian cells after viral infection questioned the functional relevance of this pathway in mammalian immunity
.
On September 22, 2021, the Zhou Xi team of Wuhan Institute of Virology of Chinese Academy of Sciences/State Key Laboratory of Virology and the land team of the Ministry of Education of Medical Molecular Virology of Fudan University/Key Laboratory of Health and Health Commission of Fudan University jointly published an online research titled “Inhibition of Viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo" research paper, the research designed a series of specifically targeting enterovirus A71 (EV-A71) encoded protein 3A, an RNAi (VSR) virus suppressor Of peptides
.
These peptides abolished the VSR function of EV-A71 in infected cells, and resulted in the accumulation of vsiRNA and the reduction of virus replication
.
These vsiRNAs are functional, as evidenced by RISC loading and silencing of target RNA
.
The effect of VSR targeting peptide (VTP) on EV-A71 and another enterovirus Coxsackie virus-A16 infection was ablated after removing Dicer1 or AGO2, the core component of the RNAi pathway
.
In vivo, VTP treatment protects mice from the lethal EV-A71 attack through detectable vsiRNA
.
The results of this study provide evidence for the functional relevance of RNAi in mammalian immunity and propose treatment strategies for infectious diseases
.
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 host cells, 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 Zhouxi team’s collaborative study found that the non-structural protein 3A of enterovirus EV71 has RNAi suppression (VSR) activity, which can prevent Dicer from cutting the viral dsRNA and producing vsiRNA; and the EV71 mutant virus lacking 3A-VSR activity It can produce a large number of vsiRNAs in the infected mammalian cells and the body to stimulate RNAi antiviral response, thus proving that RNAi as an antiviral immunity still exists in mammals, and revealing a mechanism by which human viruses escape RNAi immunity (Immunity 2017)
.
In addition, they also discovered VSR proteins encoded by many 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 revealed The molecular mechanism of its interaction with the host RNAi antiviral pathway (Cell Res.
2019, Sci Adv.
2020, J Virol.
2020, Sci China-Life Sci.
2020, Virol Sin.
2020, Viruses 2021)
.
In this study, the research team innovatively proposed a drug development concept that targets VSR to release the antiviral potential of RNAi
.
They 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
.
More importantly, 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.
The research team also found that VTP can inhibit the replication of a variety of enteroviruses and has broad-spectrum anti-intestinal virus 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, which fully proves the physiological and functional importance of RNAi as mammalian antiviral immunity
.
More importantly, from the perspective of antiviral drug development, the research is based on a new antiviral mechanism and found that VSR is a new type of drug target, and developed a first-in-class candidate for the enterovirus VSR mechanism.
Antiviral drugs provide new ideas and strategies for the development of antiviral drugs for other important viruses
.
In addition, VTP for enteroviruses has very low toxicity and antigenicity in animals, high 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
.
At the same time, the research has applied for invention patents in China, PCT, the United States, Japan, and Australia
.
Article link: https://
