| 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
|
|
WOS Category
|
CHEMISTRY, MEDICINAL
CHEMISTRY, ORGANIC
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| DNA material |
pBMSA-PA (RDB01971)
pBMSA-PB2 (RDB01969). |
