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Suzuki, Takashi; Ikeda, Kiyoshi; Koyama, Noriko; Hosokawa, Chika; Kogure, Toshihiro; Takahashi, Toshifumi; Hidari, Kazuya I.P.J.; Miyamoto, Daisei; Tanaka, Kiyoshi; Suzuki, Yasuo

doi:10.1023/a:1013617232576

Cited by 32 publications

(12 citation statements)

References 20 publications

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“…The multifunctionality of hPIV HN makes it a target of choice for the design of antiviral drugs. Several inhibitors based on the 2-deoxy-2,3-didehydro-D- N -acetylneuraminic acid (Neu5Ac2en, 1 ) scaffold, such as BCX 2798 ( 2 ) [7,8] (Figure 1A), have been designed to target hPIV-1 HN’s catalytic domain, but none have advanced to clinical studies [9,10,11,12,13].…”

Section: Introductionmentioning

confidence: 99%

Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors

Eveno

Dirr

El‐Deeb

et al. 2019

Viruses

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Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor binding activity (early stage) and receptor-destroying activity (late stage), which makes it an ideal target for antiviral drug disovery. In this study, we showed that targeting the catalytic mechanism of hPIV-1 HN by a 2α,3β-difluoro derivative of the known hPIV-1 inhibitor, BCX 2798, produced more potent inhibition of the neuraminidase function which is reflected by a stronger inhibition of viral replication. The difluorosialic acid-based inhibitor efficiently blocked the neuraminidase activity of HN for a prolonged period of time relative to its unsaturated neuraminic acid (Neu2en) analogue, BCX 2798 and produced a more efficient inhibition of the HN neuraminidase activity as well as in vitro viral replication. This prolonged inhibition of the hPIV-1 HN protein suggests covalent binding of the inhibitor to a key catalytic amino acid, making this compound a new lead for a novel class of more potent hPIV-1 mechanism-based inhibitors.

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Section: Introductionmentioning

confidence: 99%

Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors

Eveno

Dirr

El‐Deeb

et al. 2019

Viruses

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“…The spread of paramyxoviruses in tissues depends on the efficient release of viral progeny from primary infected cells, leading to further cell infections. NA inhibitors are applied extracellularly to inhibit that viral spread to neighboring cells [1, 38]. When, as shown with our mutants, receptor inactivation and receptor destruction are already finished before the process of virus budding has started, the effects of antiviral drugs should be rather directed toward preventing paramyxoviral progeny from adsorption to new, uninfected cells.…”

Section: Discussionmentioning

confidence: 99%

Neuraminidase-deficient Sendai virus HN mutants provide protection from homologous superinfection

Baumann

Neubert

2009

Arch Virol

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Binding of hemagglutinin-neuraminidase proteins (HN) to sialylated receptors initiates the infection process of several paramyxoviruses, whereas later in the viral life cycle, the neuramindase (NA) activity of newly synthesized HN destroys all receptors. Prior to NA action, expressed HN has to bind the receptor. To evaluate this HN–receptor complex with respect to receptor inactivation, three temperature-sensitive Sendai virus HN mutants carrying amino acid exchanges at positions 262, 264 and/or 461 were created that uncoupled NA activity from receptor binding at 39°C. Interestingly, at elevated temperature, when there is no detectable neuramindase activity, all infected cells are protected against homologous superinfection. Mutated HN protein on the cell surface is mainly bound to sialylated cell-surface components but can be released by treatment with NA. Thus, continuous binding to HN already inactivates the receptors quantitatively. Furthermore, mutant HN bound to receptors is prevented from being incorporated into virus particles in the absence of NA. It is shown here for the first time that during paramyxoviral infection, quantitative receptor inactivation already occurs due to binding of receptors to expressed HN protein without involvement of NA and is independent of NA activity of viral progeny. NA subsequently functions in the release of HN from the complex, coupled with desialysation of receptors. These findings could have implications for further antiviral drug development.

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“…In 2004, Portner et al reported that compounds BCX 2798 (3) and BCX 2855 (4) with modifications at C-4 and C-5 positions of 1, which were designs based on the crystal structure of the HN of Newcastle disease virus (NDV), were specific and potent inhibitors of hPIVs. 10) We demonstrated that 4-O-amidinomethyl-5, 11,12) 4-O-thiocarbamamoylmethyl-6, [11][12][13] 4-O-ethyl-7, 14) and 4-O-(2-thienyl-2-propynyl) Neu5Ac2en derivatives 8 15) have potential inhibitory activities against the sialidase from hPIV-1.…”

Section: 2)mentioning

confidence: 99%

Syntheses of 2-Deoxy-2,3-didehydro-<i>N</i>-acetylneuraminic Acid Analogues Modified by α-Acylaminoamido Groups at the C-4 Position Using Isocyanide-Based Four-Component Coupling and Biological Evaluation as Inhibitors of Human Parainfluenza Virus Type 1

Nishino

Hayakawa

Takahashi

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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Novel sialidase inhibitors 11 having an α-acylaminoamido group at the C-4 position of Neu5Ac2en 1 against human parainfluenza virus type 1 (hPIV-1) were synthesized using one-pot isocyanide-based fourcomponent condensation, and their inhibitory activities against hPIV-1 sialidase were studied. Compound 11b showed inhibitory activity (IC 50 =5.1 mm) against hPIV-1 sialidase. The degree of inhibition of 11b was much weaker than that of 1 (IC 50 =0.3 mm).Key words human parainfluenza virus type 1; sialidase inhibitor; sialic acid; 4-isocyano Neu5Ac2en derivative; isocyanide-based four-component coupling Human parainfluenza viruses (hPIVs), members of the human parainfluenza viruses (hPIVs), which are part of the Paramyxoviridae family, are important respiratory tract pathogens in infants and children. Four different types of hPIV have been identified, all of which cause a spectrum of illnesses of the upper and lower respiratory tracts of children.

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Cited by 32 publications

References 20 publications

Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors

Targeting Human Parainfluenza Virus Type-1 Haemagglutinin-Neuraminidase with Mechanism-Based Inhibitors

Neuraminidase-deficient Sendai virus HN mutants provide protection from homologous superinfection

Syntheses of 2-Deoxy-2,3-didehydro-<i>N</i>-acetylneuraminic Acid Analogues Modified by α-Acylaminoamido Groups at the C-4 Position Using Isocyanide-Based Four-Component Coupling and Biological Evaluation as Inhibitors of Human Parainfluenza Virus Type 1

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