A zanamivir dimer with prophylactic and enhanced therapeutic activity against influenza viruses

Tarbet, E. Bart; Hamilton, Stephanie; Vollmer, Almut H.; Luttick, Angela; Ng, Wendy; Pryor, Melinda J.; Hurst, Brett L.; Crawford, Simon; Smee, Donald F.; Tucker, Simon P.

doi:10.1093/jac/dku127

Cited by 16 publications

(23 citation statements)

References 26 publications

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“…Among them, BANA-206, the first achiral molecule, was reported to show sub-micromolar antiviral potency against the influenza A virus [11,12]. Some compounds have been successfully designed by the conjugation method, including compounds BTA938 [13] and ZA-7-CA [14]; their anti-influenza activity was enhanced. Based on combination principles as well as the principle of functional groups, we integrated triazole into BANA-206 on the C3 side chain and designed a series of benzoic acid derivatives to obtain potential influenza virus inhibitors with improved antiviral activity.…”

Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

Guo

et al. 2019

IJMS

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The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC 50 ) for H1N1 and H1N1-H275Y were 33.6 µM and 32.8 µM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC 50 ) of NC-5 was greater than 640 µM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.

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Section: Introductionmentioning

confidence: 99%

Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

Guo

et al. 2019

IJMS

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“…By far, the most characterized function of NA is its action as a sialidase enzyme, enabling release of new virion progeny by enzymatically cleaving sialic acids from cell surface receptors and from carbohydrate side chains on nascent virions (Gottschalk, 1958; Palese et al., 1974). When NA activity is inhibited by the use of antivirals that target the enzymatic site, or through alteration of key amino acid residues, such as those identified to be integral in the catalytic process, the budding virions aggregate on the cell surface instead of being released (Lentz et al., 1987; Tarbet et al., 2014; Yang et al., 2016). This clumping of virions is due to HA on newly released virus binding to the sialic acids expressed on receptors in the vicinity of the budding site and to carbohydrate side chains on the HA and NA of progeny viruses that still contain terminal sialic acids in the absence of NA activity.…”

Section: Na Functional Roles In Replicationmentioning

confidence: 99%

Influenza Virus Neuraminidase Structure and Functions

et al. 2019

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With the constant threat of emergence of a novel influenza virus pandemic, there must be continued evaluation of the molecular mechanisms that contribute to virulence. Although the influenza A virus surface glycoprotein neuraminidase (NA) has been studied mainly in the context of its role in viral release from cells, accumulating evidence suggests it plays an important, multifunctional role in virus infection and fitness. This review investigates the various structural features of NA, linking these with functional outcomes in viral replication. The contribution of evolving NA activity to viral attachment, entry and release of virions from infected cells, and maintenance of functional balance with the viral hemagglutinin are also discussed. Greater insight into the role of this important antiviral drug target is warranted.

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“…Remarkably, dimeric (or tethered) NA inhibitors developed by Tucker and co-workers are prospective for the clinical realization as anti-influenza agents (117)(118)(119)(120). Dimeric zanamivir conjugates were synthesized and proved to be highly potent NA inhibitors ( Figure 9) (120,121). These dimeric compounds showed broad-spectrum activity and were 10-1000 fold more potent than that of zanamivir.…”

Section: Na Inhibitors (Nais)mentioning

confidence: 99%

Progress of small molecular inhibitors in the development of anti-influenza virus agents

Wu¹,

Wu²,

Sun³

et al. 2017

Theranostics

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The influenza pandemic is a major threat to human health, and highly aggressive strains such as H1N1, H5N1 and H7N9 have emphasized the need for therapeutic strategies to combat these pathogens. Influenza anti-viral agents, especially active small molecular inhibitors play important roles in controlling pandemics while vaccines are developed. Currently, only a few drugs, which function as influenza neuraminidase (NA) inhibitors and M2 ion channel protein inhibitors, are approved in clinical. However, the acquired resistance against current anti-influenza drugs and the emerging mutations of influenza virus itself remain the major challenging unmet medical needs for influenza treatment. It is highly desirable to identify novel anti-influenza agents. This paper reviews the progress of small molecular inhibitors act as antiviral agents, which include hemagglutinin (HA) inhibitors, RNA-dependent RNA polymerase (RdRp) inhibitors, NA inhibitors and M2 ion channel protein inhibitors etc. Moreover, we also summarize new, recently reported potential targets and discuss strategies for the development of new anti-influenza virus drugs.

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A zanamivir dimer with prophylactic and enhanced therapeutic activity against influenza viruses

Abstract: In vitro and in vivo experiments showed the high antiviral activity of BTA938 for the treatment of influenza virus infections. Moreover, we demonstrated that a single dose of BTA938 is sufficient for prophylactic and therapeutic protection in mouse models.

Cited by 16 publications

References 26 publications

Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

Influenza Virus Neuraminidase Structure and Functions

Progress of small molecular inhibitors in the development of anti-influenza virus agents

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