Identification
of C5-NH2 Modified Oseltamivir
Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly
Improved Antiviral Activities and Favorable Druggability
posted on 2021-11-04, 22:03authored byHan Ju, N. Arul Murugan, Lingxin Hou, Ping Li, Laura Guizzo, Ying Zhang, Chiara Bertagnin, Xiujie Kong, Dongwei Kang, Ruifang Jia, Xiuli Ma, Ruikun Du, Vasanthanathan Poongavanam, Arianna Loregian, Bing Huang, Xinyong Liu, Peng Zhan
Our
previous efforts have proved that modifications targeting the
150-cavity of influenza neuraminidase can achieve more potent and
more selective inhibitors. In this work, four subseries of C5-NH2 modified oseltamivir derivatives were designed and synthesized
to explore every region inside the 150-cavity. Among them, compound 23d was exceptionally potent against the whole panel of Group-1
NAs with IC50 values ranging from 0.26 to 0.73 nM, being
15–53 times better than oseltamivir carboxylate (OSC) and 7–11
times better than zanamivir. In cellular assays, 23d showed
more potent or equipotent antiviral activities against corresponding
virus strains compared to OSC with no cytotoxicity. Furthermore, 23d exhibited high metabolic stability in human liver microsomes
(HLM) and low inhibitory effect on main cytochrome P450 enzymes. Notably, 23d displayed favorable druggability in vivo and potent antiviral
efficacy in the embryonated egg model and mice model. Overall, 23d appears to be a promising candidate for the treatment
of influenza virus infection.