Inhibition of human parainfluenza virus type 1 sialidase by analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid.
Eleven novel analogs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) modified at the C-4 and C-9 positions were designed and tested for their ability to inhibit sialidase of human parainfluenza virus type 1 (hPIV-1). The analogs modified by the cyanomethyl, amidinomethyl, and thiocarbamoylmethyl groups at the C-4 position exhibited potent inhibition against hPIV-1 sialidase compared with Neu5Ac2en. The most effective compound was thiocarbamoylmethyl analog (4-O-thiocarbamoylmethyl-Neu5Ac2en). The activity of 4-O-thiocarbamoylmethyl-Neu5Ac2en causing 50% enzyme inhibition at a concentration of approximately 1.0x10(-5) M was 30-fold larger than Neu5Ac2en. While, the analogs of Neu5Ac2en modified by the azido and N-acetyl groups at the C-9 showed a decrease in inhibition of sialidase compared with the 9-hydroxy analogs. In addition, 4-O-thiocarbamoylmethyl-Neu5Ac2en strongly inhibited hPIV-1 infections of Lewis lung carcinoma-monkey kidney cells in comparison with Neu5Ac2en. The present findings would provide useful information for the development of anti-human parainfluenza virus compounds.
Suzuki
T
T
Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, Shizuoka 422-8526, Japan. Suzukit@ys7.u-shizuoka-ken.ac.jp
Ikeda
K
K
Koyama
N
N
Hosokawa
C
C
Kogure
T
T
Takahashi
T
T
Jwa Hidari
K I
KI
Miyamoto
D
D
Tanaka
K
K
Suzuki
Y
Y
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010222:Parainfluenza Virus 1, Human / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; C036137:2-deoxy-2,3-dehydro-N-acetylneuraminic acid; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid