A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1–N9 Neuraminidases: Insight into Neuraminidase–Inhibitor Interactions

• Published in: Journal of medicinal chemistry 2016-05, Vol.59 (10), p.4563-4577
• Main Authors: Sriwilaijaroen, Nongluk, Magesh, Sadagopan, Imamura, Akihiro, Ando, Hiromune, Ishida, Hideharu, Sakai, Miho, Ishitsubo, Erika, Hori, Takanori, Moriya, Setsuko, Ishikawa, Takeshi, Kuwata, Kazuo, Odagiri, Takato, Tashiro, Masato, Hiramatsu, Hiroaki, Tsukamoto, Kenji, Miyagi, Taeko, Tokiwa, Hiroaki, Kiso, Makoto, Suzuki, Yasuo
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Chickens; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Madin Darby Canine Kidney Cells; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; Orthomyxoviridae - drug effects; Orthomyxoviridae - growth & development; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01863

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.