Flavivirus methyltransferase: A novel antiviral target

Hongping Dong, Bo Zhang, Pei-Yong Shi

Research output: Contribution to journalReview article

86 Citations (Scopus)

Abstract

Many flaviviruses are significant human pathogens. No effective antiviral therapy is currently available for treatment of flavivirus infections. Development of antiviral treatment against these viruses is urgently needed. The flavivirus methyltransferase (MTase) responsible for N-7 and 2′-O methylation of the viral RNA cap has recently been mapped to the N-terminal region of nonstructural protein 5. Structural and functional studies suggest that the MTase represents a novel antiviral target. Here we review current understanding of flavivirus RNA cap methylation and its implications for development of antivirals. The 5′ end of the flavivirus plus-strand RNA genome contains a type 1 cap structure (m 7GpppAmG). Flaviviruses encode a single MTase domain that catalyzes two sequential methylations of the viral RNA cap, GpppA-RNA → m 7GpppA-RNA → m 7GpppAm-RNA, using S-adenosyl-l-methionine (SAM) as the methyl donor. The two reactions require different viral RNA elements and distinct biochemical assay conditions. Despite exhibiting two distinct methylation activities, flavivirus MTase contains a single binding site for SAM in its crystal structure. Therefore, substrate GpppA-RNA must be re-positioned to accept the N-7 and 2′-O methyl groups from SAM during the two methylation reactions. Structure-guided mutagenesis studies indeed revealed two distinct sets of amino acids on the enzyme surface that are specifically required for N-7 and 2′-O methylation. In the context of virus, West Nile viruses (WNVs) defective in N-7 methylation are non-replicative; however, WNVs defective in 2′-O methylation are attenuated and can protect mice from subsequent wild-type WNV challenge. Collectively, the results demonstrate that the N-7 MTase represents a novel target for flavivirus therapy.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalAntiviral Research
Volume80
Issue number1
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Flavivirus
Methyltransferases
Methylation
Antiviral Agents
RNA Caps
West Nile virus
RNA
Viral RNA
Methionine
Flavivirus Infections
Viruses
Mutagenesis
Binding Sites
Genome
Amino Acids
Enzymes
Therapeutics

Keywords

  • Antiviral therapy
  • Dengue virus
  • Flavivirus NS5
  • Flavivirus replication
  • Japanese encephalitis virus
  • Methyltransferase
  • Tick-borne encephalitis virus
  • West Nile virus
  • Yellow fever virus

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Flavivirus methyltransferase : A novel antiviral target. / Dong, Hongping; Zhang, Bo; Shi, Pei-Yong.

In: Antiviral Research, Vol. 80, No. 1, 10.2008, p. 1-10.

Research output: Contribution to journalReview article

Dong, Hongping ; Zhang, Bo ; Shi, Pei-Yong. / Flavivirus methyltransferase : A novel antiviral target. In: Antiviral Research. 2008 ; Vol. 80, No. 1. pp. 1-10.
@article{3a0f0a6e48b74ad3a900d721957a02d8,
title = "Flavivirus methyltransferase: A novel antiviral target",
abstract = "Many flaviviruses are significant human pathogens. No effective antiviral therapy is currently available for treatment of flavivirus infections. Development of antiviral treatment against these viruses is urgently needed. The flavivirus methyltransferase (MTase) responsible for N-7 and 2′-O methylation of the viral RNA cap has recently been mapped to the N-terminal region of nonstructural protein 5. Structural and functional studies suggest that the MTase represents a novel antiviral target. Here we review current understanding of flavivirus RNA cap methylation and its implications for development of antivirals. The 5′ end of the flavivirus plus-strand RNA genome contains a type 1 cap structure (m 7GpppAmG). Flaviviruses encode a single MTase domain that catalyzes two sequential methylations of the viral RNA cap, GpppA-RNA → m 7GpppA-RNA → m 7GpppAm-RNA, using S-adenosyl-l-methionine (SAM) as the methyl donor. The two reactions require different viral RNA elements and distinct biochemical assay conditions. Despite exhibiting two distinct methylation activities, flavivirus MTase contains a single binding site for SAM in its crystal structure. Therefore, substrate GpppA-RNA must be re-positioned to accept the N-7 and 2′-O methyl groups from SAM during the two methylation reactions. Structure-guided mutagenesis studies indeed revealed two distinct sets of amino acids on the enzyme surface that are specifically required for N-7 and 2′-O methylation. In the context of virus, West Nile viruses (WNVs) defective in N-7 methylation are non-replicative; however, WNVs defective in 2′-O methylation are attenuated and can protect mice from subsequent wild-type WNV challenge. Collectively, the results demonstrate that the N-7 MTase represents a novel target for flavivirus therapy.",
keywords = "Antiviral therapy, Dengue virus, Flavivirus NS5, Flavivirus replication, Japanese encephalitis virus, Methyltransferase, Tick-borne encephalitis virus, West Nile virus, Yellow fever virus",
author = "Hongping Dong and Bo Zhang and Pei-Yong Shi",
year = "2008",
month = "10",
doi = "10.1016/j.antiviral.2008.05.003",
language = "English (US)",
volume = "80",
pages = "1--10",
journal = "Antiviral Research",
issn = "0166-3542",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Flavivirus methyltransferase

T2 - A novel antiviral target

AU - Dong, Hongping

AU - Zhang, Bo

AU - Shi, Pei-Yong

PY - 2008/10

Y1 - 2008/10

N2 - Many flaviviruses are significant human pathogens. No effective antiviral therapy is currently available for treatment of flavivirus infections. Development of antiviral treatment against these viruses is urgently needed. The flavivirus methyltransferase (MTase) responsible for N-7 and 2′-O methylation of the viral RNA cap has recently been mapped to the N-terminal region of nonstructural protein 5. Structural and functional studies suggest that the MTase represents a novel antiviral target. Here we review current understanding of flavivirus RNA cap methylation and its implications for development of antivirals. The 5′ end of the flavivirus plus-strand RNA genome contains a type 1 cap structure (m 7GpppAmG). Flaviviruses encode a single MTase domain that catalyzes two sequential methylations of the viral RNA cap, GpppA-RNA → m 7GpppA-RNA → m 7GpppAm-RNA, using S-adenosyl-l-methionine (SAM) as the methyl donor. The two reactions require different viral RNA elements and distinct biochemical assay conditions. Despite exhibiting two distinct methylation activities, flavivirus MTase contains a single binding site for SAM in its crystal structure. Therefore, substrate GpppA-RNA must be re-positioned to accept the N-7 and 2′-O methyl groups from SAM during the two methylation reactions. Structure-guided mutagenesis studies indeed revealed two distinct sets of amino acids on the enzyme surface that are specifically required for N-7 and 2′-O methylation. In the context of virus, West Nile viruses (WNVs) defective in N-7 methylation are non-replicative; however, WNVs defective in 2′-O methylation are attenuated and can protect mice from subsequent wild-type WNV challenge. Collectively, the results demonstrate that the N-7 MTase represents a novel target for flavivirus therapy.

AB - Many flaviviruses are significant human pathogens. No effective antiviral therapy is currently available for treatment of flavivirus infections. Development of antiviral treatment against these viruses is urgently needed. The flavivirus methyltransferase (MTase) responsible for N-7 and 2′-O methylation of the viral RNA cap has recently been mapped to the N-terminal region of nonstructural protein 5. Structural and functional studies suggest that the MTase represents a novel antiviral target. Here we review current understanding of flavivirus RNA cap methylation and its implications for development of antivirals. The 5′ end of the flavivirus plus-strand RNA genome contains a type 1 cap structure (m 7GpppAmG). Flaviviruses encode a single MTase domain that catalyzes two sequential methylations of the viral RNA cap, GpppA-RNA → m 7GpppA-RNA → m 7GpppAm-RNA, using S-adenosyl-l-methionine (SAM) as the methyl donor. The two reactions require different viral RNA elements and distinct biochemical assay conditions. Despite exhibiting two distinct methylation activities, flavivirus MTase contains a single binding site for SAM in its crystal structure. Therefore, substrate GpppA-RNA must be re-positioned to accept the N-7 and 2′-O methyl groups from SAM during the two methylation reactions. Structure-guided mutagenesis studies indeed revealed two distinct sets of amino acids on the enzyme surface that are specifically required for N-7 and 2′-O methylation. In the context of virus, West Nile viruses (WNVs) defective in N-7 methylation are non-replicative; however, WNVs defective in 2′-O methylation are attenuated and can protect mice from subsequent wild-type WNV challenge. Collectively, the results demonstrate that the N-7 MTase represents a novel target for flavivirus therapy.

KW - Antiviral therapy

KW - Dengue virus

KW - Flavivirus NS5

KW - Flavivirus replication

KW - Japanese encephalitis virus

KW - Methyltransferase

KW - Tick-borne encephalitis virus

KW - West Nile virus

KW - Yellow fever virus

UR - http://www.scopus.com/inward/record.url?scp=50049109958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50049109958&partnerID=8YFLogxK

U2 - 10.1016/j.antiviral.2008.05.003

DO - 10.1016/j.antiviral.2008.05.003

M3 - Review article

C2 - 18571739

AN - SCOPUS:50049109958

VL - 80

SP - 1

EP - 10

JO - Antiviral Research

JF - Antiviral Research

SN - 0166-3542

IS - 1

ER -