The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor

Varghese, Joseph; McKimm-Breschkin, Jennifer L.; Caldwell, J. B.; Kortt, Alexander A.; Colman, Peter M.

doi:10.1002/prot.340140302

Cited by 390 publications

(309 citation statements)

References 29 publications

Supporting

Mentioning

296

Contrasting

Unclassified

Order By: Relevance

“…Early X-ray crystal structures of NA heads complexed with sialic acid were solved for N2 22 , N9 2324 and type B 25 NAs. These showed a conserved 6-bladed propeller structure, each blade made up of four anti-parallel beta sheets stabilized by disulfide bonds and connected by loops of variable length.…”

Section: Neuraminidase Structural Domainsmentioning

confidence: 99%

“…Under a variety of soaking conditions, sialic acid was seen bound in both the active site and the HB site of all four monomers. In the active site the sialic acid is in the twisted boat conformation that may result from its tight binding preceding catalysis 22,63,64 , while the sialic acid in the HB site is in the chair conformation as in N9 NB site and in HA 32,59 . Interestingly, although sialic acid in solution exists 95% as the β anomer, only the α configuration is seen in the HB binding site (Figure 3), which may explain the difficulty in locating the second sialic acid in N9 NA and the high concentration of sialic acid needed before the sialic acid is clearly seen.…”

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

See 1 more Smart Citation

Influenza neuraminidase

Air

2011

Influenza Resp Viruses

215

216

View full text Add to dashboard Cite

Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been largely ignored as a vaccine target despite evidence that inclusion of neuraminidase in the subunit vaccine gives increased protection. This article describes current knowledge on the structure, enzyme activity and antigenic significance of neuraminidase.

show abstract

Section: Neuraminidase Structural Domainsmentioning

confidence: 99%

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

Influenza neuraminidase

Air

2011

Influenza Resp Viruses

215

216

View full text Add to dashboard Cite

show abstract

“…Neuraminidase (NA) inhibitors, such as zanamivir and oseltamivir, were synthesized after the crystal structures of influenza NA complexes with sialic acid and the sialic acid derivative 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid were determined [77,78]. These inhibitors block the active site of the NA enzyme, inhibiting virus release from infected cells and spread within the respiratory tract [79].…”

Section: Prevention and Controlmentioning

confidence: 99%

H5N1 avian influenza virus: an overview

2007

View full text Add to dashboard Cite

Avian influenza virus (H5N1) emerged in Hong Kong in 1997, causing severe human disease. In recent years, several outbreaks have been reported in different parts of Asia, Europe and Africa, raising concerns of dissemination of a new and highly lethal influenza pandemic. Although H5N1 has not been capable of sustaining human-tohuman transmission, the ability of the virus to undergo variation due to mutations and reassortment, clearly poses the possibility of viral adaptation to the human species. For this reason the World Health Organization has established that we are now in a phase of pandemic alert. Preparing for an influenza pandemic involves a great deal of awareness necessary to stop initial outbreaks, through the use of case recognition, sensitive and rapid diagnostic methods, appropriate therapeutic and preventive measures to reduce spread. Influenza pandemic preparedness involves coordinated pharmacologic and vaccinal strategies, as well as containment measures such as travel restrictions and quarantine approaches.

show abstract

“…NA is a good therapeutic target because its active site is highly conserved among the many characterized in£u-enza A and in£uenza B viral strains and subtypes (Colman et al 1983;Burmeister et al 1992;Varghese et al 1992). This conservation suggests that NA inhibitors could protect against newly emerged, potentially pandemic in£u-enza strains.…”

Section: Introductionmentioning

confidence: 99%

“…This conservation suggests that NA inhibitors could protect against newly emerged, potentially pandemic in£u-enza strains. X-ray crystallography has been used for determining the structure of NA complexed with sialic acid (Burmeister et al 1992;Varghese et al 1992), which is its natural substrate or with 2-deoxy-2,3-didehydro-Nacetylneuraminic acid (DANA), which is a transition state analogue of sialic acid with non-selective NA inhibitory activity (Bossart-Whitaker et al 1993). This work has led to rational drug design of NA inhibitors that are highly speci¢c to the in£uenza virus (Von Itzstein et al 1993;Kim et al 1997;Babu et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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

Dc¹,

Fowler²,

Bush³

2001

Phil. Trans. R. Soc. Lond. B

View full text Add to dashboard Cite

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.

show abstract

The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor

Cited by 390 publications

References 29 publications

Influenza neuraminidase

Influenza neuraminidase

H5N1 avian influenza virus: an overview

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

Contact Info

Product

Resources

About