2. Academic Validation
  3. Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo

Inhibition of viral suppressor of RNAi proteins by designer peptides protects from enteroviral infection in vivo

  • Immunity. 2021 Oct 12;54(10):2231-2244.e6. doi: 10.1016/j.immuni.2021.08.027.
Yuan Fang 1,  Zezhong Liu 2,  Yang Qiu 3,  Jing Kong 3,  Yuhong Fu 2,  Yujie Liu 1,  Chong Wang 4,  Jia Quan 1,  Qian Wang 2,  Wei Xu 2,  Lei Yin 5,  Jie Cui 6,  Yi Xu 7,  Stephen Curry 8,  Shibo Jiang 2,  Lu Lu 9,  Xi Zhou 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences (CAS), Wuhan 430071, China.
  • 2 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences (CAS), Wuhan 430071, China.
  • 4 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences (CAS), Wuhan 430071, China; Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China.
  • 5 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 6 CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, CAS, Shanghai 200031, China.
  • 7 Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510120, China.
  • 8 Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
  • 9 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: lul@fudan.edu.cn.
  • 10 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences (CAS), Wuhan 430071, China. Electronic address: zhouxi@wh.iov.cn.
PMID: 34555337 DOI: 10.1016/j.immuni.2021.08.027
Abstract

RNA interference (RNAi) is the major Antiviral mechanism in Plants and invertebrates, but the absence of detectable viral (v)siRNAs in mammalian cells upon viral Infection has questioned the functional relevance of this pathway in mammalian immunity. We designed a series of Peptides specifically targeting Enterovirus A71 (EV-A71)-encoded protein 3A, a viral suppressor of RNAi (VSR). These Peptides abrogated the VSR function of EV-A71 in infected cells and resulted in the accumulation of vsiRNAs and reduced viral replication. These vsiRNAs were functional, as evidenced by RISC-loading and silencing of target RNAs. The effects of VSR-targeting Peptides (VTPs) on Infection with EV-A71 as well as another Enterovirus, Coxsackievirus-A16, were ablated upon deletion of Dicer1 or AGO2, core components of the RNAi pathway. In vivo, VTP treatment protected mice against lethal EV-A71 challenge, with detectable vsiRNAs. Our findings provide evidence for the functional relevance of RNAi in mammalian immunity and present a therapeutic strategy for infectious disease.

Keywords

EV-A71; HFMD; VSR; antiviral RNAi immunity; antiviral drug; enterovirus; hand-foot-and-mouth disease; peptide drug; viral suppressor of RNAi.

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