A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor

Gang Zou, Francesc Puig-Basagoiti, Bo Zhang, Min Qing, Liqiang Chen, Krzysztof W. Pankiewicz, Krzysztof Felczak, Zhiming Yuan, Pei-Yong Shi

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val → Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound's potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis.

Original languageEnglish (US)
Pages (from-to)242-252
Number of pages11
JournalVirology
Volume384
Issue number1
DOIs
StatePublished - Feb 5 2009
Externally publishedYes

Fingerprint

Flavivirus
West Nile virus
Amino Acid Substitution
Peptides
Antiviral Agents
Viral RNA
West Nile Fever
Western Equine Encephalitis Viruses
Rhabdoviridae
Yellow fever virus
Alphavirus
Vesicular Stomatitis
Dengue
Endoplasmic Reticulum
Hydroxyl Radical
lycorine
Cell Culture Techniques
RNA
Viruses
Amino Acids

Keywords

  • Antiviral
  • Flavivirus 2K peptide
  • Flavivirus replication
  • Viral resistance
  • West Nile virus

ASJC Scopus subject areas

  • Virology

Cite this

A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor. / Zou, Gang; Puig-Basagoiti, Francesc; Zhang, Bo; Qing, Min; Chen, Liqiang; Pankiewicz, Krzysztof W.; Felczak, Krzysztof; Yuan, Zhiming; Shi, Pei-Yong.

In: Virology, Vol. 384, No. 1, 05.02.2009, p. 242-252.

Research output: Contribution to journalArticle

Zou, Gang ; Puig-Basagoiti, Francesc ; Zhang, Bo ; Qing, Min ; Chen, Liqiang ; Pankiewicz, Krzysztof W. ; Felczak, Krzysztof ; Yuan, Zhiming ; Shi, Pei-Yong. / A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor. In: Virology. 2009 ; Vol. 384, No. 1. pp. 242-252.
@article{24cfc0d49f744fe19687d74b1824434e,
title = "A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor",
abstract = "Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val → Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound's potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis.",
keywords = "Antiviral, Flavivirus 2K peptide, Flavivirus replication, Viral resistance, West Nile virus",
author = "Gang Zou and Francesc Puig-Basagoiti and Bo Zhang and Min Qing and Liqiang Chen and Pankiewicz, {Krzysztof W.} and Krzysztof Felczak and Zhiming Yuan and Pei-Yong Shi",
year = "2009",
month = "2",
day = "5",
doi = "10.1016/j.virol.2008.11.003",
language = "English (US)",
volume = "384",
pages = "242--252",
journal = "Virology",
issn = "0042-6822",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor

AU - Zou, Gang

AU - Puig-Basagoiti, Francesc

AU - Zhang, Bo

AU - Qing, Min

AU - Chen, Liqiang

AU - Pankiewicz, Krzysztof W.

AU - Felczak, Krzysztof

AU - Yuan, Zhiming

AU - Shi, Pei-Yong

PY - 2009/2/5

Y1 - 2009/2/5

N2 - Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val → Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound's potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis.

AB - Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val → Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound's potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis.

KW - Antiviral

KW - Flavivirus 2K peptide

KW - Flavivirus replication

KW - Viral resistance

KW - West Nile virus

UR - http://www.scopus.com/inward/record.url?scp=58649100667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58649100667&partnerID=8YFLogxK

U2 - 10.1016/j.virol.2008.11.003

DO - 10.1016/j.virol.2008.11.003

M3 - Article

VL - 384

SP - 242

EP - 252

JO - Virology

JF - Virology

SN - 0042-6822

IS - 1

ER -