RRC ID 6868
Author Iwai Y, Takahashi H, Hatakeyama D, Motoshima K, Ishikawa M, Sugita K, Hashimoto Y, Harada Y, Itamura S, Odagiri T, Tashiro M, Sei Y, Yamaguchi K, Kuzuhara T.
Title Anti-influenza activity of phenethylphenylphthalimide analogs derived from thalidomide.
Journal Bioorg Med Chem
Abstract Swine-origin influenza A virus has caused pandemics throughout the world and influenza A is regarded as a serious global health issue. Hence, novel drugs that will target these viruses are very desirable. Influenza A expresses an RNA polymerase essential for its transcription and replication which comprises PA, PB1, and PB2 subunits. We identified potential novel anti-influenza agents from a screen of 34 synthesized phenethylphenylphthalimide analogs derived from thalidomide (PPT analogs). For this screen we used a PA endonuclease inhibition assay, a PB2 pathogenicity-determinant domain-binding assay, and an anti-influenza A virus assay. Three PPT analogs, PPT-65, PPT-66, and PPT-67, were found to both inhibit PA endonuclease activity and retard the growth of influenza A, suggesting a correlation between their activities. PPT-28 was also found to inhibit the growth of influenza A. These four analogs have a 3,4-dihydroxyphenethyl group in common. We also discuss the possibility that 3,4-dihydroxyphenethyl group flexibility may play an important functional role in PA endonuclease inhibition. Another analog harboring a dimethoxyphenethyl group, PPT-62, showed PB2 pathogenicity-determinant domain-binding activity, but did not inhibit the growth of the virus. Our present results indicate the utility of the PA endonuclease assay in the screening of anti-influenza drugs and are therefore useful for future strategies to develop novel anti-influenza A drugs and for mapping the function of the influenza A RNA polymerase subunits.
Volume 18(14)
Pages 5379-90
Published 2010-7-15
DOI 10.1016/j.bmc.2010.05.035
PII S0968-0896(10)00454-2
PMID 20538468
MeSH Animals Antiviral Agents / chemical synthesis Antiviral Agents / chemistry* Antiviral Agents / pharmacology* Cell Line DNA-Directed RNA Polymerases / metabolism Dogs Humans Influenza A virus / drug effects* Influenza A virus / enzymology Influenza, Human / drug therapy* Orthomyxoviridae Infections / drug therapy Phthalimides / chemical synthesis Phthalimides / chemistry Phthalimides / pharmacology Stilbenes / chemical synthesis Stilbenes / chemistry Stilbenes / pharmacology Thalidomide / chemical synthesis Thalidomide / chemistry* Thalidomide / pharmacology*
IF 3.073
Times Cited 35
DNA material pBMSA-PA (RDB01971) pBMSA-PB2 (RDB01969).