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Tytuł pozycji:

Antiviral Peptides Targeting the Helicase Activity of Enterovirus Nonstructural Protein 2C.

Tytuł:
Antiviral Peptides Targeting the Helicase Activity of Enterovirus Nonstructural Protein 2C.
Autorzy:
Fang Y; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Wang C; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.; The University of Chinese Academy of Sciences, Beijing, China.
Wang C; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Yang R; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.; The University of Chinese Academy of Sciences, Beijing, China.
Bai P; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
Zhang XY; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Kong J; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.; The University of Chinese Academy of Sciences, Beijing, China.
Yin L; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
Qiu Y; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.; The University of Chinese Academy of Sciences, Beijing, China.
Zhou X; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China .; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.; The University of Chinese Academy of Sciences, Beijing, China.
Źródło:
Journal of virology [J Virol] 2021 May 24; Vol. 95 (12). Date of Electronic Publication: 2021 May 24 (Print Publication: 2021).
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.
MeSH Terms:
Antiviral Agents/*pharmacology
Carrier Proteins/*antagonists & inhibitors
Enterovirus A, Human/*drug effects
Enterovirus Infections/*drug therapy
Peptides/*pharmacology
RNA Helicases/*antagonists & inhibitors
Viral Nonstructural Proteins/*antagonists & inhibitors
Animals ; Antiviral Agents/chemistry ; Antiviral Agents/therapeutic use ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Cell Line ; Drug Design ; Enterovirus A, Human/chemistry ; Enterovirus A, Human/physiology ; Enterovirus B, Human/drug effects ; Enterovirus B, Human/physiology ; Enterovirus Infections/virology ; Humans ; Mice ; Mice, Inbred ICR ; Peptides/chemistry ; Peptides/therapeutic use ; RNA Helicases/metabolism ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
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Contributed Indexing:
Keywords: antimicrobial peptides; antiviral agents; enteroviral 2C; enterovirus; helicase
Substance Nomenclature:
0 (Antiviral Agents)
0 (Carrier Proteins)
0 (Peptides)
0 (Viral Nonstructural Proteins)
EC 3.6.1.- (2C protein, viral)
EC 3.6.4.13 (RNA Helicases)
Entry Date(s):
Date Created: 20210401 Date Completed: 20210615 Latest Revision: 20211125
Update Code:
20240104
PubMed Central ID:
PMC8315976
DOI:
10.1128/JVI.02324-20
PMID:
33789997
Czasopismo naukowe
Enteroviruses belong to the genus Enterovirus of the family Picornaviridae and include four human enterovirus groups (EV-A to -D): the epidemic of enteroviruses such as human enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) is a threat to global public health. Enteroviral protein 2C is the most conserved nonstructural protein among all enteroviruses and possesses RNA helicase activity that plays pivotal roles during enteroviral life cycles, which makes 2C an attractive target for developing antienterovirus drugs. In this study, we designed a peptide, named 2CL, based on the structure of EV-A71 2C. This peptide effectively impaired the oligomerization of EV-A71 2C protein and inhibited the RNA helicase activities of 2C proteins encoded by EV-A71 and CVA16, both of which belong to EV-A, and showed potent antiviral efficacy against EV-A71 and CVA16 in cells. Moreover, the 2CL treatment elicited a strong in vivo protective efficacy against lethal EV-A71 challenge. In addition, the antiviral strategy of targeting the 2C helicase activity can be applied to inhibit the replication of EV-B. Either 2CL or B-2CL, the peptide redesigned based on the 2CL-corresponding sequence of EV-Bs, could exert effective antiviral activity against two important EV-Bs, coxsackievirus B3 and echovirus 11. Together, our findings demonstrated that targeting the helicase activity of 2C with a rationally designed peptide is an efficient antiviral strategy against enteroviruses, and 2CL and B-2CL show promising clinical potential to be further developed as broad-spectrum antienterovirus drugs. IMPORTANCE Enteroviruses are a large group of positive-sense single-stranded RNA viruses and include numerous human pathogens, such as enterovirus A71 (EV-A71), coxsackieviruses, and echoviruses. However, no approved EV antiviral drugs are available. Enteroviral 2C is the most conserved nonstructural protein among all enteroviruses and contains the RNA helicase activity critical for the viral life cycle. Herein, according to the structure of EV-A71 2C, we designed a peptide that effectively inhibited the RNA helicase activities of EV-A71- and coxsackievirus A16 (CVA16)-encoded 2C proteins. Moreover, this peptide exerted potent antiviral effects against EV-A71 and CVA16 in cells and elicited therapeutic efficacy against lethal EV-A71 challenge in vivo Furthermore, we demonstrate that the strategy of targeting the 2C helicase activity can be used for other relevant enteroviruses, including coxsackievirus B3 and echovirus 11. In summary, our findings provide compelling evidence that the designed peptides targeting the helicase activity of 2C could be broad-spectrum antivirals for enteroviruses.
(Copyright © 2021 American Society for Microbiology.)

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