TY - JOUR
T1 - Anti-influenza activity of phenethylphenylphthalimide analogs derived from thalidomide
AU - Iwai, Yuma
AU - Takahashi, Hitoshi
AU - Hatakeyama, Dai
AU - Motoshima, Kazunori
AU - Ishikawa, Minoru
AU - Sugita, Kazuyuki
AU - Hashimoto, Yuichi
AU - Harada, Yuichi
AU - Itamura, Shigeyuki
AU - Odagiri, Takato
AU - Tashiro, Masato
AU - Sei, Yoshihisa
AU - Yamaguchi, Kentaro
AU - Kuzuhara, Takashi
N1 - Funding Information:
The influenza virus (A/PR/8/34) RNA polymerase PA and PB2 plasmids, pBMSA-PA and pBMSA-PB2, were provided by the DNA Bank, RIKEN BioResource Center (Tsukuba, Japan; originally deposited by Dr. Susumu Nakada) with the support of National Bio-Resources Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT). This work was supported in part by a Grant-in-Aid for Young Scientists (Start-up) 20870037 (D.H.) from the Japan Society for the Promotion of Science (JSPS), Japan .
PY - 2010/7/15
Y1 - 2010/7/15
N2 - 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.
AB - 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.
KW - Endonuclease
KW - Influenza
KW - Phenethylphenylphthalimide
KW - RNA polymerase
KW - Thalidomide
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U2 - 10.1016/j.bmc.2010.05.035
DO - 10.1016/j.bmc.2010.05.035
M3 - Article
C2 - 20538468
AN - SCOPUS:77955334015
SN - 0968-0896
VL - 18
SP - 5379
EP - 5390
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 14
ER -