A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1-N9 Neuraminidases: Insight into Neuraminidase-Inhibitor Interactions.
People throughout the world continue to be at risk for death from influenza A virus, which is always creating a new variant. Here we present a new effective and specific anti-influenza viral neuraminidase (viNA) inhibitor, 9-cyclopropylcarbonylamino-4-guanidino-Neu5Ac2en (cPro-GUN). Like zanamivir, it is highly effective against N1-N9 avian and N1-N2 human viNAs, including H274Y oseltamivir-resistant N1 viNA, due to its C-6 portion still being anchored in the active site, different from the disruption of oseltamivir's C-6 anchoring by H274Y mutation. Unlike zanamivir, no sialidase inhibitory activity has been observed for cPro-GUN against huNeu1-huNeu4 enzymes. Broad efficacy of cPro-GUN against avian and human influenza viruses in cell cultures comparable to its sialidase inhibitory activities makes cPro-GUN ideal for further development for safe therapeutic or prophylactic use against both seasonal and pandemic influenza.
Department of Preclinical Sciences, Faculty of Medicine, Thammasat University , Pathumthani 12120, Thailand.|Health Science Hills, College of Life and Health Sciences, Chubu University , Aichi 487-8501, Japan.
Nongluk
N
Sriwilaijaroen
Sadagopan
S
Magesh
Akihiro
A
Imamura
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University , Kyoto 606-8501, Japan.
Hiromune
H
Ando
Hideharu
H
Ishida
Miho
M
Sakai
Erika
E
Ishitsubo
Takanori
T
Hori
Division of Cancer Glycosylation Research, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University , Sendai 981-8558, Japan.
Setsuko
S
Moriya
Takeshi
T
Ishikawa
Kazuo
K
Kuwata
Influenza Virus Research Center, National Institute of Infectious Diseases , Tokyo 208-0011, Japan.
Takato
T
Odagiri
Influenza Virus Research Center, National Institute of Infectious Diseases , Tokyo 208-0011, Japan.
Masato
M
Tashiro
Health Science Hills, College of Life and Health Sciences, Chubu University , Aichi 487-8501, Japan.
Hiroaki
H
Hiramatsu
Research Team for Zoonotic Diseases, National Institute of Animal Health , Ibaraki 305-0856, Japan.
Kenji
K
Tsukamoto
Division of Cancer Glycosylation Research, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University , Sendai 981-8558, Japan.
Taeko
T
Miyagi
Hiroaki
H
Tokiwa
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University , Kyoto 606-8501, Japan.
Makoto
M
Kiso
Health Science Hills, College of Life and Health Sciences, Chubu University , Aichi 487-8501, Japan.
Yasuo
Y
Suzuki
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002645:Chickens; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009439:Neuraminidase