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Responsible editor | Xi RNAi is a highly conserved post-transcriptional gene silencing mechanism in eukaryotes.
It is also a highly effective antiviral natural immune mechanism.
It is considered to be the most important antiviral in fungi, plants and invertebrates.
Function
.
When the virus infects the host cell, the double-stranded RNA (dsRNA) produced by viral RNA replication is recognized by the Dicer protein of the RNAi pathway and cut into viral-derived small interfering RNA (viral siRNA, vsiRNA), and these vsiRNAs are further assembled into RNA-induced silencing The complex RISC mediates the degradation of viral RNA in infected cells
.
At the same time, many viruses have been found to escape RNAi antiviral immunity by encoding "Viral Suppressor of RNAi (VSR)"
.
On September 22, 2021, the Zhou Xi team of Wuhan Institute of Virology, Chinese Academy of Sciences/State Key Laboratory of Virology and the land team of the Ministry of Education of Medical Molecular Virology/Key Laboratory of Health Commission of Fudan University published an online publication in Immunity magazine titled " Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo" research paper reveals for the first time that the rational design of peptide inhibitors specifically targeting enterovirus RNAi suppressors (VSR) can effectively "unlock" viruses VSR inhibits RNAi, fully releases the antiviral immune function of RNAi, exhibits good antiviral activity at the level of cells and animals, and has high safety, and has the potential for further clinical development
.
In fact, although RNAi has long been recognized as the antiviral immune mechanism of eukaryotes, some studies have found that virus-derived vsiRNA cannot be detected in many virus-infected mammalian somatic cells.
It also has antiviral immune function
.
One view is that RNAi, as one of the oldest antiviral mechanisms in eukaryotes, has become an "evolutionary relic" under the background of the development of interferon and other antiviral mechanisms in mammals.
Then there is anti-viral function
.
In 2017, Zhou Xi's team and Qin Chengfeng's team worked together and found that the non-structural protein 3A of enterovirus EV71 has VSR activity, which can prevent Dicer from cutting viral dsRNA and the production of vsiRNA; and 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 the RNAi antiviral response, thus proving that RNAi as an antiviral immunity still exists in mammals (Immunity 2017)
.
Since then, they have discovered that RNAi plays an important antiviral immune effect in human neural precursor cells and brain-like organs produced by them, and can inhibit Zika virus infection and microcephaly (Cell Res.
2019 cover article); and found The NS2A protein of dengue virus, Japanese encephalitis virus, Zika virus and other flaviviruses has a VSR function, which can assist flaviviruses to escape RNAi immunity in the mosquitoes and mammals they infect, and affect the cross-species replication and pathogenicity of flaviviruses ( Sci Adv.
2020)
.
In addition, Zhou Xi's team also discovered the VSR protein encoded by a variety of important human viruses such as SARS-CoV-2, Alpha virus, Rubella virus, and hepatitis C virus, and revealed the molecular mechanism of its antagonism to the RNAi pathway
.
The above research work strongly confirmed that RNAi as a kind of antiviral immunity does exist in mammals
.
However, as a mammalian antiviral immune mechanism, is RNAi important in function and physiology? Does it have a therapeutic application prospect? These key scientific questions need to be answered further
.
In this study, the research team innovatively proposed a drug development concept that targets VSR to release the antiviral potential of RNAi
.
Using the enterovirus EV71 as a model, they designed several VSR-targeting peptides (VTP) for the key functional regions of the VSR of its 3A protein
.
The study found that these VTPs can directly bind to the 3A protein, and through competition, the 3A inhibits RNAi in EV71-infected somatic cells, thereby inducing the production of a large number of viral vsiRNAs; these vsiRNAs are then assembled into RISC to mediate infection The degradation of EV71 RNA in cells effectively inhibits EV71 replication
.
More importantly, VTP can also stimulate the RNAi antiviral response in mice, produce a large amount of vsiRNA, inhibit the replication of EV71 in various tissues and organs throughout the body, and rescue the death and clinical symptoms of mice caused by EV71 infection
.
It is worth noting that VTP cannot play an antiviral effect in cells and mice infected with EV71 mutant virus lacking 3A-VSR function, as well as in cells lacking Dicer or AGO2, which proves that its mechanism of action is indeed targeted 3A-VSR, and depends on the RNAi pathway
.
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 well inhibit the replication of a variety of enteroviruses and has broad-spectrum resistance to enteroviruses.
Active
.
In summary, this study confirmed for the first time that VTP-specific targeting of VSR can effectively release RNAi antiviral immunity in mammalian somatic cells and animals infected with wild-type virus
.
From a basic theoretical point of view, the "unlocked" RNAi of VTP can exert a highly effective antiviral effect, which fully proves the physiological and functional importance of RNAi as a mammalian antiviral immunity
.
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 antiviral drug against enterovirus 3A-VSR.
It provides new ideas and strategies for the development of antiviral drugs for other important viruses
.
In addition, VTP against enterovirus 3A-VSR has very low animal toxicity and antigenicity, 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
.
Dr.
Fang Yuan from the Wuhan Institute of Virology, Chinese Academy of Sciences/State Key Laboratory of Virology, and Qiu Yang, a young researcher, and Dr.
Liu Zezhong from the Ministry of Education/Key Laboratory of Medical Molecular Virology, Fudan University, are the co-first authors of the paper, Zhou Xi The researcher and the Lulu researcher are the co-corresponding authors
.
This research has applied for invention patents in many countries including China, PCT, the United States, Japan and Australia
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
08.
027 Reprinting instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights , The offender must be investigated
.
It is also a highly effective antiviral natural immune mechanism.
It is considered to be the most important antiviral in fungi, plants and invertebrates.
Function
.
When the virus infects the host cell, the double-stranded RNA (dsRNA) produced by viral RNA replication is recognized by the Dicer protein of the RNAi pathway and cut into viral-derived small interfering RNA (viral siRNA, vsiRNA), and these vsiRNAs are further assembled into RNA-induced silencing The complex RISC mediates the degradation of viral RNA in infected cells
.
At the same time, many viruses have been found to escape RNAi antiviral immunity by encoding "Viral Suppressor of RNAi (VSR)"
.
On September 22, 2021, the Zhou Xi team of Wuhan Institute of Virology, Chinese Academy of Sciences/State Key Laboratory of Virology and the land team of the Ministry of Education of Medical Molecular Virology/Key Laboratory of Health Commission of Fudan University published an online publication in Immunity magazine titled " Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo" research paper reveals for the first time that the rational design of peptide inhibitors specifically targeting enterovirus RNAi suppressors (VSR) can effectively "unlock" viruses VSR inhibits RNAi, fully releases the antiviral immune function of RNAi, exhibits good antiviral activity at the level of cells and animals, and has high safety, and has the potential for further clinical development
.
In fact, although RNAi has long been recognized as the antiviral immune mechanism of eukaryotes, some studies have found that virus-derived vsiRNA cannot be detected in many virus-infected mammalian somatic cells.
It also has antiviral immune function
.
One view is that RNAi, as one of the oldest antiviral mechanisms in eukaryotes, has become an "evolutionary relic" under the background of the development of interferon and other antiviral mechanisms in mammals.
Then there is anti-viral function
.
In 2017, Zhou Xi's team and Qin Chengfeng's team worked together and found that the non-structural protein 3A of enterovirus EV71 has VSR activity, which can prevent Dicer from cutting viral dsRNA and the production of vsiRNA; and 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 the RNAi antiviral response, thus proving that RNAi as an antiviral immunity still exists in mammals (Immunity 2017)
.
Since then, they have discovered that RNAi plays an important antiviral immune effect in human neural precursor cells and brain-like organs produced by them, and can inhibit Zika virus infection and microcephaly (Cell Res.
2019 cover article); and found The NS2A protein of dengue virus, Japanese encephalitis virus, Zika virus and other flaviviruses has a VSR function, which can assist flaviviruses to escape RNAi immunity in the mosquitoes and mammals they infect, and affect the cross-species replication and pathogenicity of flaviviruses ( Sci Adv.
2020)
.
In addition, Zhou Xi's team also discovered the VSR protein encoded by a variety of important human viruses such as SARS-CoV-2, Alpha virus, Rubella virus, and hepatitis C virus, and revealed the molecular mechanism of its antagonism to the RNAi pathway
.
The above research work strongly confirmed that RNAi as a kind of antiviral immunity does exist in mammals
.
However, as a mammalian antiviral immune mechanism, is RNAi important in function and physiology? Does it have a therapeutic application prospect? These key scientific questions need to be answered further
.
In this study, the research team innovatively proposed a drug development concept that targets VSR to release the antiviral potential of RNAi
.
Using the enterovirus EV71 as a model, they designed several VSR-targeting peptides (VTP) for the key functional regions of the VSR of its 3A protein
.
The study found that these VTPs can directly bind to the 3A protein, and through competition, the 3A inhibits RNAi in EV71-infected somatic cells, thereby inducing the production of a large number of viral vsiRNAs; these vsiRNAs are then assembled into RISC to mediate infection The degradation of EV71 RNA in cells effectively inhibits EV71 replication
.
More importantly, VTP can also stimulate the RNAi antiviral response in mice, produce a large amount of vsiRNA, inhibit the replication of EV71 in various tissues and organs throughout the body, and rescue the death and clinical symptoms of mice caused by EV71 infection
.
It is worth noting that VTP cannot play an antiviral effect in cells and mice infected with EV71 mutant virus lacking 3A-VSR function, as well as in cells lacking Dicer or AGO2, which proves that its mechanism of action is indeed targeted 3A-VSR, and depends on the RNAi pathway
.
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 well inhibit the replication of a variety of enteroviruses and has broad-spectrum resistance to enteroviruses.
Active
.
In summary, this study confirmed for the first time that VTP-specific targeting of VSR can effectively release RNAi antiviral immunity in mammalian somatic cells and animals infected with wild-type virus
.
From a basic theoretical point of view, the "unlocked" RNAi of VTP can exert a highly effective antiviral effect, which fully proves the physiological and functional importance of RNAi as a mammalian antiviral immunity
.
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 antiviral drug against enterovirus 3A-VSR.
It provides new ideas and strategies for the development of antiviral drugs for other important viruses
.
In addition, VTP against enterovirus 3A-VSR has very low animal toxicity and antigenicity, 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
.
Dr.
Fang Yuan from the Wuhan Institute of Virology, Chinese Academy of Sciences/State Key Laboratory of Virology, and Qiu Yang, a young researcher, and Dr.
Liu Zezhong from the Ministry of Education/Key Laboratory of Medical Molecular Virology, Fudan University, are the co-first authors of the paper, Zhou Xi The researcher and the Lulu researcher are the co-corresponding authors
.
This research has applied for invention patents in many countries including China, PCT, the United States, Japan and Australia
.
Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
08.
027 Reprinting instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights , The offender must be investigated
.
