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Abstract
Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.
Acknowledgements
We gratefully acknowledge the financial support from the National Natural Science Foundation of China (NSFC no. 81773574); Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31); Foreign cultural and educational experts Project (GXL20200015001); Shandong modern agricultural technology and industry system (SDAIT-21–06); Key Research and Development Program of Shandong Province (2022CXGC010606); China Postdoctoral Science Foundation (2022M711938); Natural Science Foundation of Jiangsu Province (SBK2023041680); Associazione Italiana per la Ricerca sul Cancro, AIRC, grants IG 2016 - ID. 18855 and IG 2021 - ID. 25899 (to A.L.); Ministero dell’Istruzione, dell’Università e della Ricerca, PRIN 2017-cod. 2017KM79NN (to A.L.); Fondazione Cassa di Risparmio di Padova e Rovigo-Bando Ricerca Covid-2019 No. 55777 2020.0162-ARREST-COV: AntiviRal PROTAC-Enhanced Small-molecule Therapeutics against COronaViruses (to A.L.).
Author contributions
Jiwei Zhang and Chuanfeng Liu: Conceptualisation, Methodology, Formal analysis, Investigation, Resources, Data Curation, Writing - Original Draft, Visualisation
Ruifang Jia and Jian Zhang: Supervision, Writing - Review & Editing, Methodology
Xujie Zhang: Software
Chiara Bertagnin, Anna Bonomini, Laura Guizzo: Resource (Provision of study materials for the in vitro anti-influenza virus activity in MDCK cells)
Yuanmin Jiang, Huinan Jia, Shuzhen Jia: Resource, Data Curation
Xiuli Ma: Resource (Provision of study materials)
Arianna Loregian: Resource (Provision of study materials for the in vitro anti-influenza virus activity in MDCK cells), Writing - Review & Editing, Supervision, Project administration
Bing Huange, Peng Zhan, Xinyong Liu: Writing - Review & Editing, Supervision, Project administration, Funding acquisition
Disclosure statement
No potential conflict of interest was reported by the authors.