Complexity in Influenza Virus Targeted Drug Design: Interaction with Human Sialidases

Chavas, Leonard M. G.; Kato, Ryuichi; Suzuki, Nobuhiro; Itzstein, Mark von; Mann, Maretta; Thomson, Robin Joy; Dyason, Jeffrey Clifford; McKimm-Breschkin, Jennifer L.; Fusi, Paola; Tringali, Cristina; Venerando, Bruno; Tettamanti, Guido; Monti, Eugenio; Wakatsuki, Soichi

doi:10.1021/jm100078r

Cited by 64 publications

(75 citation statements)

References 24 publications

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“…Assays were conducted using methods previously reported from our department. 36,37 The data for inhibition, obtained for all the 4α-amino substituted derivatives, compared with those obtained for the parent a Each value represents the mean ± standard deviation of two or three independent experiments carried out in triplicate.…”

Section: Resultsmentioning

confidence: 99%

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases

Rota¹,

Allevi²,

Agnolin³

et al. 2012

Org. Biomol. Chem.

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A simple protocol for the synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid, with a secondary cyclic amine (morpholine or piperidine) at the 4α position, has been set-up, starting from peracetylated N-acetylneuraminic acid methyl ester that undergoes, sequentially to its direct N-transacylation followed by a C-4 amination, a β-elimination, and a selective hydrolysis of the ester functions, without affecting the sensitive perfluorinated amide.

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Section: Resultsmentioning

confidence: 99%

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases

Rota¹,

Allevi²,

Agnolin³

et al. 2012

Org. Biomol. Chem.

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“…The differences in orientation of the guanidino group in 8 may contribute to the retained activity of this inhibitor against influenza viruses with a Glu119 mutation that have reduced susceptibility to zanamivir [162]. In binding with the human sialidase Neu2, the cyclopentane derivative 8 appeared to be stabilized mostly by the carbox ylic acid group, with fewer overall hydrogen bonds than were seen for zanamivir, providing a rationale for the weaker inhibitory activity of 8 against Neu2 compared to zanamivir [125].…”

Section: A Sialidase Inhibitor Based On a Cyclopentane Scaffold: The mentioning

confidence: 99%

“…Against Neu2 and Neu3, this inhibition is slightly stronger than that of Neu5Ac2en 14. For Neu2 this has been attributed, based on X-ray structures of the Neu2:5 and Neu2:14 complexes, to the formation of additional hydrogen bonds to the C4 guanidino group of 5 [125]. The IC 50 (6.8 μM) for 5 against the plasma membrane Neu3 is substantially ( 1000-fold) greater than that observed for 5 against influenza virus sialidases (IC 50 ∼ 2 nM) [124].…”

Section: Selectivity For Influenza Virus Sialidase Over Human Sialidasesmentioning

confidence: 99%

“…This led ultimately to compound 8, which inhibited both influenza A and B virus sialidases at nanomolar levels (inhibition against a range of strains: A, IC 50 0.1-1.4 nM; B, 0.6-11 nM [159]) (reviewed in [161]). Lead compound 8 was selective for inhibition of the viral sialidases, with inhibition of human Neu2, for example, only at high micromolar levels (8: K i 330 μM; zanamivir 5: K i 17 μM [125]). …”

Section: A Sialidase Inhibitor Based On a Cyclopentane Scaffold: The mentioning

confidence: 99%

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Development of Influenza Virus Sialidase Inhibitors

Pascolutti

Thomson

Itzstein

2016

Methods and Principles in Medicinal Chemistry

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“…A recent study has shown that although recombinant human sialidases are not affected by oseltamivir, peramivir and zanamivir may inhibit these enzymes at high concentrations. 6 To screen for a possible underlying mild neuraminidase deficiency (sialidosis) in our patient, we assayed urinary oligosaccharide excretion, which was normal.…”

Section: Go To Sectionmentioning

confidence: 99%

Clinical Reasoning: An unexpected diagnosis in a 4-month-old infant with lethargy and H1N1 influenza

Hyslop¹,

Droker²,

Jansen³

2011

Neurology

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A 4 month-old former full-term male infant presented with 4 days of lethargy, fussiness, low-grade fever, and dehydration, prompting hospital admission. His mother had tested positive for H1N1 influenza the week before, and treatment with oseltamivir was started. Oseltamivir treatment was started empirically in the infant, but he was brought in for emergency care for progressively worsening symptoms, including poor breastfeeding and decreased urine output. He was otherwise previously healthy and developmentally normal and lived with his parents and 4 siblings on a farm in rural Washington.On admission, the patient was febrile, lethargic, and dehydrated. After an episode of emesis and subsequent increased respiratory effort, he was intubated and transferred to the intensive care unit. At the time of the initial neurology service consultation, on hospital day 2, he had recently received doses of morphine and fentanyl but was responsive to gentle physical stimulation. Although he did not track visual stimuli, he had intact horizontal eye movements on oculocephalic testing and 4-mm briskly reactive pupils bilaterally. His gag reflex was weak, and he appeared to have mild facial diplegia, but this was difficult to assess because of endotracheal tube taping. Spontaneous extremity movements were infrequent, and although his resting position was normal, appendicular tone was mildly low. His reflexes were 1ϩ at the brachioradialis, biceps, knees, and ankles. Plantar responses were upgoing.Results of initial electrolyte analyses and complete blood count were normal, and C-reactive protein level was 3.7 mg/dL (normal Ͻ0.7 mg/dL). Results of a head CT scan and routine CSF studies were normal. Blood and CSF cultures remained negative. CSF herpes simplex virus 1 and 2, enterovirus, and parechovirus PCR assays yielded no detectable copies. Results of nasal wash fluorescent antibody testing and PCR were positive for influenza A, subtype H1N1. Brain MRI showed normal results. The serum creatine kinase level was Ͻ20 IU/L, and evaluation for metabolic disorders was unremarkable. His lethargy was attributed to an influenzaassociated encephalopathy. Questions for consideration:1. What are the neurologic symptoms of H1N1 influenza in the pediatric population? 2. What aspects of the hospital care decrease the sensitivity of the neurologic examination? GO TO SECTION 2

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Complexity in Influenza Virus Targeted Drug Design: Interaction with Human Sialidases

Cited by 64 publications

References 24 publications

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases

Development of Influenza Virus Sialidase Inhibitors

Clinical Reasoning: An unexpected diagnosis in a 4-month-old infant with lethargy and H1N1 influenza

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