A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor.
Lycorine potently inhibits flaviviruses in cell culture. At 1.2-microM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 10(2)- to 10(4)-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.
Zou
Gang
G
New York State Department of Health, Wadsworth Center, USA.
Puig-Basagoiti
Francesc
F
Zhang
Bo
B
Qing
Min
M
Chen
Liqiang
L
Pankiewicz
Krzysztof W
KW
Felczak
Krzysztof
K
Yuan
Zhiming
Z
Shi
Pei-Yong
PY
D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology*; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000187:drug effects; D024882:Drug Resistance, Viral; D010617:Phenanthridines / Q000494:pharmacology*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000187:drug effects / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects / Q000235:genetics*
D047151:Amaryllidaceae Alkaloids; D000998:Antiviral Agents; C080106:NS4A protein, flavivirus; C080107:NS4B protein, flavivirus; D010617:Phenanthridines; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C015330:lycorine