Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid

Meindl, Peter; Bodo, G.; Palese, Peter; Schulman, Jerome L.; Tuppy, H.

doi:10.1016/0042-6822(74)90080-4

Cited by 287 publications

(144 citation statements)

References 15 publications

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“…Based upon what is known about the mechanism of action of NAIs,29, 30 it is theoretically possible that treatment might be ineffective [tending to produce an odds ratio (OR) close to 1] but rather implausible that it would be genuinely harmful, producing an OR > 1 as we measured. Instead, we surmise that NAIs were often prescribed after the development of pneumonia or clinical deterioration; furthermore, patients with IRP were admitted to hospital a median of 4 days from symptom onset, compared to 2 days for those with no pneumonia.…”

Section: Discussionmentioning

confidence: 99%

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Muthuri¹,

Venkatesan²,

Myles³

et al. 2016

Influenza Resp Viruses

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BackgroundThe impact of neuraminidase inhibitors (NAIs) on influenza‐related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection.MethodsA worldwide meta‐analysis of individual participant data from 20 634 hospitalised patients with laboratory‐confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) ‘pandemic influenza’. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids.ResultsOf 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64–1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44–1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71–1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55–0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54–0·85; P = 0·001)].ConclusionsEarly NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

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Section: Discussionmentioning

confidence: 99%

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Muthuri¹,

Venkatesan²,

Myles³

et al. 2016

Influenza Resp Viruses

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“…A number of analogues of NeuSAc2en were synthesized during the 1970s, and the most potent of these as a neuraminidase inhibitor was the trifluoracetyl derivative with a Ki of 0.8 pM (Meindl et al, 1974).…”

Section: Inhibitorsmentioning

confidence: 99%

Influenza virus neuraminidase: Structure, antibodies, and inhibitors

Colman¹

1994

Protein Science

314

224

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The determination of the 3-dimensional structure of the influenza virus neuraminidase in 1983 has served as a platform for understanding interactions between antibodies and protein antigens, for investigating antigenic variation in influenza viruses, and for devising new inhibitors of the enzyme. That work is reviewed here, together with more recent developments that have resulted in one of the inhibitors entering clinical trials as an anti-influenza virus drug.

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“…The crystal structure of the in£uenza NA complexed with sialic acid (¢gure 1a) or with DANA (¢gure 1b), which inhibits NA activity (Meindl et al 1974), has revealed that the NA active site is composed of four binding pockets where the major functional groups of sialic acid and DANA are positioned: (i) an acidic pocket in which three arginine residues form hydrogen bonds with the carboxylic acid side chain of DANA, (ii) a hydrophobic pocket bound by the glycerol side chain of DANA, (iii) a hydrophobic pocket occupied by the acetamido group of DANA, and (iv) a negatively charged pocket occupied by the C4-hydroxyl group of DANA. An ordered water molecule mediates the negative charges in the fourth pocket.…”

Section: The Structural Development Of a New Na Inhibitormentioning

confidence: 99%

RWJ-270201 (BCX-1812): a novel neuraminidase inhibitor for influenza

Dc¹,

Fowler²,

Bush³

2001

Phil. Trans. R. Soc. Lond. B

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The in£uenza virus neuraminidase (NA) is important in the pathogenesis of infection and, thus, is an attractive target for agents used in the treatment and prophylaxis of in£uenza. This article describes preclinical and early clinical data related to RWJ-270201 (BCX-1812), a novel, orally active NA inhibitor that was rationally designed for having potent and selective activity against in£uenza A and B viruses. RWJ-270201 is a unique NA inhibitor with a cyclopentane ring structure and high selectivity for the in£u-enza NA. RWJ-270201 has e¤cacy comparable to or better than earlier NA inhibitors against a wide range of in£uenza A and B isolates, including recently emerged and avian strains, both in vitro and in a lethal murine model of in£uenza. Based on the high selectivity and e¤cacy of RWJ-270201 against both type A and B in£uenza strains in preclinical studies as well as murine pharmacodynamic studies supporting the potential for once-daily administration, clinical trials were initiated in order to determine the tolerability and antiviral activity of RWJ-270201 in humans. To date, clinical studies have indicated that RWJ-270201 is well tolerated and has antiviral activity in human experimental in£uenza models when administered orally once daily.

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Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid

Cited by 287 publications

References 15 publications

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Influenza virus neuraminidase: Structure, antibodies, and inhibitors

RWJ-270201 (BCX-1812): a novel neuraminidase inhibitor for influenza

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