BPR2-D2 targeting viral ribonucleoprotein complex-associated function inhibits oseltamivir-resistant influenza viruses.

Abstract

OBJECTIVES:

The emergence of oseltamivir-resistant viruses raised the global threat with regard to influenza virus infection. To develop alternative antiviral agents against influenza virus infection is significant and urgent.

METHODS:

A neutralization test was applied as a screening assay and a plaque reduction assay was used for confirmation. Expression plasmids for viral ribonucleoproteins (RNPs) and a plasmid that allowed expression of a pseudoviral reporter RNA were transfected into cells to investigate the effects of a novel antiviral compound on viral RNA synthesis.

RESULTS:

BPR2-D2 was identified as a novel inhibitor against influenza virus from a hit obtained from high throughput screening of 20 000 or more compounds. BPR2-D2 exhibited an excellent antiviral efficacy for the oseltamivir-resistant virus (EC(50) ranging from 0.021 to 0.040 microM). No resistant virus was produced throughout 20 passages in the presence of BPR2-D2, whereas oseltamivir-resistant virus was generated at passage 8 using the same experimental system. A molecular target other than neuraminidase (NA) was found because BPR2-D2 inhibited the synthesis of viral RNA that was driven by influenza viral RNP in a transfection assay. BPR2-D2 also exhibited a broad antiviral spectrum against various strains of influenza A and influenza B viruses.

CONCLUSIONS:

BPR2-D2 was identified as a novel inhibitor of influenza virus. It may target viral RNPs that are responsible for viral RNA synthesis. Targeting different molecules compared with NA allows BPR2-D2 to inhibit oseltamivir-resistant viruses.

• Authors: Shin-Ru Shih, Jim-Tong Horng, Leo L M Poon, Tzu-Chun Chen, Jiann-Yih Yeh, Hsing-Pang Hsieh, Sung-Nain Tseng, Chiayn Chiang, Wan-Ling Li, Yu-Sheng Chao, John T-A Hsu
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 65 Issue 1 Pg. 63-71 (Jan 2010) ISSN: 1460-2091 [Electronic] England
• PMID: 19892833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Ribonucleoproteins
• Viral Proteins
• Oseltamivir

Topics

• Antiviral Agents (pharmacology)
• Cell Line
• Drug Evaluation, Preclinical
• Drug Resistance, Viral
• Humans
• Inhibitory Concentration 50
• Molecular Structure
• Neutralization Tests
• Orthomyxoviridae (drug effects, genetics)
• Oseltamivir (pharmacology)
• Ribonucleoproteins (antagonists & inhibitors, genetics)
• Transfection
• Viral Plaque Assay
• Viral Proteins (antagonists & inhibitors, genetics)