Inhibitors of the human neuraminidase enzymes

Cairo, Christopher W.

doi:10.1039/c4md00089g

Cited by 33 publications

(65 citation statements)

References 100 publications

(181 reference statements)

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“…Current treatments for influenza include inhaled zanamivir (Relenza), oral oseltamivir (Tamiflu) and intravenous peramivir (Rapivab), which were developed as substrate analogs targeting viral NA (von Itzstein et al 1993 ; Lagoja and De Clercq 2008 ; Cairo 2014 ). Previous studies have shown that NA-VLP purified using sucrose gradient centrifugation exhibit enzymatic activity (Mohan et al 2010 ; Garcia et al 2014 ).…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Fig. 6 a, product is uniquely formed in the presence of NA-VLP and the enzyme activity is reversed by the addition of the inhibitor DANA (Neu5Ac2en), a transition state analog and the parent compound of FDA-approved NA inhibitors (von Itzstein et al 1993 ; Lagoja and De Clercq 2008 ; Cairo 2014 ). Importantly, control measurements using VLP prepared in the absence of NA expression (native-VLP), in which p24 levels were used to normalize the amount of VLP in the samples, exhibited no activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In a first step we showed that NA embedded in VLP exhibits specific enzyme activity and that this activity is inhibited by DANA (Fig. 6 ), a parent compound of current influenza antivirals (von Itzstein et al 1993 ; Lagoja and De Clercq 2008 ; Cairo 2014 ). Subsequently, a full analysis of NA activity and inhibition was performed by NMR (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…We next demonstrated the utility of VLP applied to NA, a high priority target for influenza antivirals (von Itzstein et al 1993 ; Lagoja and De Clercq 2008 ; Cairo 2014 ). In a first step we showed that NA embedded in VLP exhibits specific enzyme activity and that this activity is inhibited by DANA (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Application of virus-like particles (VLP) to NMR characterization of viral membrane protein interactions

et al. 2016

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The membrane proteins of viruses play critical roles in the virus life cycle and are attractive targets for therapeutic intervention. Virus Like Particles (VLP) present the possibility to study the biochemical and biophysical properties of viral membrane proteins in their native environment. Specifically, the VLP constructs contain the entire protein sequence and are comprised of native membrane components including lipids, cholesterol, carbohydrates and cellular proteins. In this study we prepare VLP containing full-length hemagglutinin (HA) or neuraminidase (NA) from influenza and characterize their interactions with small molecule inhibitors. Using HA-VLP, we first show that VLP samples prepared using the standard sucrose gradient purification scheme contain significant amounts of serum proteins, which exhibit high potential for non-specific interactions, thereby complicating NMR studies of ligand-target interactions. We then show that the serum contaminants may be largely removed with the addition of a gel filtration chromatography step. Next, using HA-VLP we demonstrate that WaterLOGSY (WL) NMR is significantly more sensitive than Saturation Transfer Difference (STD) NMR for the study of ligand interactions with membrane bound targets. In addition, we compare the ligand orientation to HA embedded in VLP with that of recombinant HA by STD NMR. In a subsequent step, using NA-VLP we characterize the kinetic and binding properties of substrate analogs and inhibitors of NA, including study of the H274Y-NA mutant, which leads to wide spread resistance to current influenza antivirals. In summary, our work suggests that VLP have high potential to become standard tools in biochemical and biophysical studies of viral membrane proteins, particularly when VLP are highly purified and combined with control VLP containing native membrane proteins.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Application of virus-like particles (VLP) to NMR characterization of viral membrane protein interactions

et al. 2016

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“…The acrosome appears to contain a further reservoir of sialidases, which are released physiologically during the acrosome reaction prior to fertilization (8,12). Because NEU1 and NEU3 together are able to desialylate several different glycoconjugates (␣2,3-, ␣2,6-, and ␣2,8-sialylated), a significant restructuring of the glycocalyx can be expected (13)(14)(15).…”

mentioning

confidence: 99%

Desialylation of Spermatozoa and Epithelial Cell Glycocalyx Is a Consequence of Bacterial Infection of the Epididymis

Khosravi

Michel

Galuska³

et al. 2016

Journal of Biological Chemistry

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Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in humans. In men, pathogens can also spread to the genital tract via the continuous ductal system, eliciting bacterial prostatitis and/or epididymo-orchitis. Antibiotic treatment usually clears pathogens in acute epididymitis; however, the fertility of patients can be permanently impaired. Because a premature acrosome reaction was observed in an UPEC epididymitis mouse model, and sialidases on the sperm surface are considered to be activated via proteases of the acrosome, we aimed to investigate whether alterations of the sialome of epididymal spermatozoa and surrounding epithelial cells occur during UPEC infection. In UPEC-elicited acute epididymitis in mice, a substantial loss of N-acetylneuraminic acid residues was detected in epididymal spermatozoa and epithelial cells using combined laser microdissection/HPLC-ESI-MS analysis. In support, a substantial reduction of sialic acid residues bound to the surface of spermatozoa was documented in men with a recent history of E. coli-associated epididymitis. In vitro, such an UPEC induced N-acetylneuraminic acid release from human spermatozoa was effectively counteracted by a sialidase inhibitor. These findings strongly suggest a substantial remodeling of the glycocalyx of spermatozoa and epididymal epithelial cells by endogenous sialidases after a premature acrosome reaction during acute epididymitis.

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Polyvalent Transition‐State Analogues of Sialyl Substrates Strongly Inhibit Bacterial Sialidases**

assailly

Bridot

Saumonneau

et al. 2021

Chemistry A European J

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Inhibitors of the human neuraminidase enzymes

Abstract: A review of known small molecule inhibitors and substrates of the human neuraminidase enzymes.

Cited by 33 publications

References 100 publications

Application of virus-like particles (VLP) to NMR characterization of viral membrane protein interactions

Application of virus-like particles (VLP) to NMR characterization of viral membrane protein interactions

Desialylation of Spermatozoa and Epithelial Cell Glycocalyx Is a Consequence of Bacterial Infection of the Epididymis

Polyvalent Transition‐State Analogues of Sialyl Substrates Strongly Inhibit Bacterial Sialidases**

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