Divalent oseltamivir analogues as potent influenza neuraminidase inhibitors

Yan, Zhong-Li; Liu, Ao-Yun; Wei, Xia-Xia; Zhang, Zhuang; Qin, Long; Yu, Qun; Yu, Peng; Lu, Kui; Yang, Yang

doi:10.1016/j.carres.2019.03.012

Cited by 18 publications

(10 citation statements)

References 43 publications

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“…A multivalent NAI based on OC has previously been reported, but the OC moiety was linked through its carboxylate and effects were modest in NA inhibition, likely due to the fact that the carboxylate plays a role in binding to NA. 31 Conjugation of 12 to a series of four spacers with vastly different lengths but similar chemical features and rigidities also proved possible. The motif of alternating glucose, triazole, and occasional benzene rings was previously shown to lead to greatly enhanced divalent binding versus a flexible PEG structure.…”

Section: Discussionmentioning

confidence: 99%

Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors

Wei

Duca

et al. 2022

J. Med. Chem.

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Divalent inhibitors of the neuraminidase enzyme (NA) of the Influenza A virus were synthesized with vastly different spacers. The spacers varied from 14 to 56 atoms and were relatively rigid by way of the building blocks and their connection by CuAAC. As the ligand for these constructs, a Δ 4 -β- d -glucoronide was used, which can be prepared form N -acetyl glucosamine. This ligand showed good NA inhibitory potency but with room for improvement by multivalency enhancement. The synthesized compounds showed modest potency enhancement in NA activity assays but a sizeable potency increase in a 4-day cytopathic effect assay. The demonstration that the compounds can also inhibit hemagglutinin in addition to NA may be the cause of the enhancement.

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Section: Discussionmentioning

confidence: 99%

Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors

Wei

Duca

et al. 2022

J. Med. Chem.

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“…Yang and co-workers 84 have prepared a series of divalent guanidino oseltamivir and oseltamivir analogues via a click reaction ( Fig. 12 ).…”

Section: Neuraminidase Inhibitors (Nais)mentioning

confidence: 99%

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

et al. 2021

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“…One novel and innovative modification sees a 32 Å polyglycol addition linking two oseltamivir monomers, forming “Divalent oseltamivir” (9). The cross-linking effect allows the occupancy of more than one SA active site in the tetramer and translates to a 68-fold increase in inhibitory potency in vitro compared to oseltamivir ( Yan et al, 2019 ). This strategy is currently being explored as an exciting method of increasing drug potency and selectivity (as mammalian SAs are not tetrameric), breathing new life into compounds that are prone to resistance.…”

Section: Introductionmentioning

confidence: 99%

Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease

Bowles

Gloster

2021

Front. Mol. Biosci.

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Sialidases (SAs) and sialyltransferases (STs), the enzymes responsible for removing and adding sialic acid to other glycans, play essential roles in viruses, bacteria, parasites, and humans. Sialic acid is often the terminal sugar on glycans protruding from the cell surface in humans and is an important component for recognition and cell function. Pathogens have evolved to exploit this and use sialic acid to either “cloak” themselves, ensuring they remain undetected, or as a mechanism to enable release of virus progeny. The development of inhibitors against SAs and STs therefore provides the opportunity to target a range of diseases. Inhibitors targeting viral, bacterial, or parasitic enzymes can directly target their pathogenicity in humans. Excellent examples of this can be found with the anti-influenza drugs Zanamivir (Relenza™, GlaxoSmithKline) and Oseltamivir (Tamiflu™, Roche and Gilead), which have been used in the clinic for over two decades. However, the development of resistance against these drugs means there is an ongoing need for novel potent and specific inhibitors. Humans possess 20 STs and four SAs that play essential roles in cellular function, but have also been implicated in cancer progression, as glycans on many cancer cells are found to be hyper-sialylated. Whilst much remains unknown about how STs function in relation to disease, it is clear that specific inhibitors of them can serve both as tools to gain a better understanding of their activity and form the basis for development of anti-cancer drugs. Here we review the recent developments in the design of SA and ST inhibitors against pathogens and humans.

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Divalent oseltamivir analogues as potent influenza neuraminidase inhibitors

Cited by 18 publications

References 43 publications

Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors

Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease

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