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Peramivir and laninamivir susceptibility of circulating influenza A and B viruses.

ABSTRACT: Influenza viruses collected from regions of Asia, Africa and Oceania between 2009 and 2012 were tested for their susceptibility to two new neuraminidase inhibitors, peramivir and laninamivir. All viruses tested had normal laninamivir inhibition. However, 3·2% (19/599) of A(H1N1)pdm09 viruses had highly reduced peramivir inhibition (due to H275Y NA mutation) and <1% (6/1238) of influenza B viruses had reduced or highly reduced peramivir inhibition, with single occurrence of variants containing I221T, A245T, K360E, A395E, D432G and a combined G145R+Y142H mutation. These data demonstrate that despite an increase in H275Y variants in 2011, there was no marked change in the frequency of peramivir- or laninamivir-resistant variants following the market release of the drugs in Japan in 2010.

SUBMITTER: Leang SK

PROVIDER: S-EPMC4186459 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Peramivir and laninamivir susceptibility of circulating influenza A and B viruses.

Leang Sook-Kwan SK Kwok Simon S Sullivan Sheena G SG Maurer-Stroh Sebastian S Kelso Anne A Barr Ian G IG Hurt Aeron C AC

Influenza and other respiratory viruses 20140301 2

Influenza viruses collected from regions of Asia, Africa and Oceania between 2009 and 2012 were tested for their susceptibility to two new neuraminidase inhibitors, peramivir and laninamivir. All viruses tested had normal laninamivir inhibition. However, 3·2% (19/599) of A(H1N1)pdm09 viruses had highly reduced peramivir inhibition (due to H275Y NA mutation) and <1% (6/1238) of influenza B viruses had reduced or highly reduced peramivir inhibition, with single occurrence of variants containing I2 ...[more]

PMID: 24734292

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Project description:The H7N9 virus attaches itself to the human cell receptor protein containing the polysaccharide that terminates with sialic acid. The mutation of neuraminidase at residue E119 has been explored experimentally. However, there is no adequate information on the substitution with E119V in peramivir at the intermolecular level. Therefore, a good knowledge of the interatomic interactions is a prerequisite in understanding its transmission mode and subsequent effective inhibitions of the sialic acid receptor cleavage by neuraminidase. Herein, we investigated the mechanism and dynamism on the susceptibility of the E119V mutation on the peramivir-neuraminidase complex relative to the wildtype complex at the intermolecular level. This study aims to investigate the impact of the 119V substitution on the neuraminidase-peramivir complex and unveil the residues responsible for the complex conformations. We employed molecular dynamic (MD) simulations and extensive post-MD analyses in the study. These extensive computational investigations were carried out on the wildtype and the E119V mutant complex of the protein for holistic insights in unveiling the effects of this mutation on the binding affinity and the conformational terrain of peramivir-neuraminidase E119V mutation. The calculated total binding energy (ΔGbind) for the peramivir wildtype is -49.09 ± 0.13 kcal/mol, while the E119V mutant is -58.55 ± 0.15 kcal/mol. The increase in binding energy (9.46 kcal/mol) is consistent with other post-MD analyses results, confirming that E119V substitution confers a higher degree of stability on the protein complex. This study promises to proffer contributory insight and additional knowledge that would enhance future drug designs and help in the fight targeted at controlling the avian influenza H7N9 virus. Therefore, we suggest that experimentalists collaborate with computational chemists for all investigations of this topic, as we have done in our previous studies.

Project description:ObjectiveThis report presents a review of the efficacy and safety of peramivir, a neuraminidase inhibitor that was granted Emergency Use Authorization by the US Food and Drug Administration (FDA) from October 23, 2009 to June 23, 2010 during the 2009 H1N1 pandemic.MethodsLiterature was accessed via PubMed (January 2000-April 2014) using several search terms: peramivir; BCX-1812; RWJ 270201; H1N1, influenza; antivirals; and neuraminidase inhibitors. The peramivir manufacturers, Shionogi and Co Ltd and BioCryst Pharmaceuticals, were contacted to obtain unpublished data and information presented at recent scientific meetings. Information was obtained from the Centers for Disease Control and Prevention (CDC) and from US FDA websites. English-language and Japanese-language reports in the literature were reviewed and selected based on relevance, along with information from the CDC, US FDA, and the drug manufacturers.ResultsWe obtained eleven clinical trial reports of intravenous peramivir, two of which described comparisons with oseltamivir. Seven of nine other recently reported published studies was a dose-response study. Clinical reports of critically ill patients and pediatric patients infected with pandemic H1N1 described that early treatment significantly decreased mortality. Peramivir administered at 300 mg once daily in adult patients with influenza significantly reduces the time to alleviation of symptoms or fever compared to placebo. It is likely to be as effective as other neuraminidase inhibitors.ConclusionAlthough peramivir shows efficacy for the treatment of seasonal and pH1N1 influenza, it has not received US FDA approval. Peramivir is used safely and efficiently in hospitalized adult and pediatric patients with suspected or laboratory-confirmed influenza. Peramivir might be a beneficial alternative antiviral treatment for many patients, including those unable to receive inhaled or oral neuraminidase inhibitors, or those requiring nonintravenous drug delivery.

Dataset Information

Peramivir and laninamivir susceptibility of circulating influenza A and B viruses.

Publications

Peramivir and laninamivir susceptibility of circulating influenza A and B viruses.

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