Influenza B viruses

Viruses that contain amino acid substitutions in the sialidase that impart resistance to the developed inhibitors have been isolated from serial passage of virus in the presence of drug in cell culture and from the clinical setting (reviewed in McKimm-Breschkin 2000 Zambon and Hayden 2001 Cinatl et al. 2007a Reece 2007). In addition, influenza B virus variants with reduced drug sensitivity have been isolated from previously untreated patients (Hurt et al. 2006 Hatakeyama et al. 2007). The types of mutations that are observed are sub-type specific. The mutations present in variants isolated from clinical samples are shown in Table 1, and their locations within the sialidase active site are shown diagrammatically in Fig. 9. 

B neuraminidase and its complex with sialic acid. Embo J 11 49-56 Burmeister WP, Henrissat B, Bosso C, Cusack S, Ruigrok RW (1993) Influenza B virus neuraminidase can synthesize its own inhibitor. Structure 1 19-26 Calfee DP, Hayden FG (1998) New approaches to influenza chemotherapy neuraminidase inhibitors, Drugs 56 537-553... 

Gubareva LV, Matrosovich MN, Brenner MK, Bethell RC, Webster RG (1998) Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus, J Infect Dis 178 1257-1262... 

Hagiwara T, Kijima-Suda I, Ido T, Ohrui H, Tomita K (1994) Inhibition of bacterial and viral sialidases by 3-fluoro-V-acetyIneuraminic acid, Carbohydr Res 263 167-172 Haskell TH, Peterson FE, Watson D, Plessas NR, Culbertson T (1970) Neuraminidase inhibition and viral chemotherapy, J Med Chem 13 697-704 Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Ichikawa M, Kimura K, Kiso M, Shimizu H, Kawakami C, Koike K, Mitamura K, Kawaoka Y (2007) Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors, JAMA 297 1435-1442 Hay AJ (1992) The action of adamantanamines against influenza A viruses inhibition of the M2 ion channel protein, Semin Virol 3 21-30... 

Hurt AC, lanneUo P, Jachno K, Komadina N, Hampson AW, Barr IG, McKimm-Breschkin JL (2006) Neuraminidase inhibitor-resistant and -sensitive influenza B viruses isolated from an untreated human patient, Antimicrob Agents Chemother 50 1872-1874 Hurt AC, Selleck P, Komadina N, Shaw R, Brown L, Barr IG (2007) Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antiviral Res 73 228-231... 

Oseltamivir and zanamivir are neuraminidase inhibitors that have activity against both influenza A and influenza B viruses. When administered within 48 hours of the onset of illness, oseltamivir and zanamivir may reduce the duration of illness by approximately 1 day versus placebo. 

Removal of the C-8 and C-9 hydroxy groups in order to produce a hydro-phobic side-chain, gave such derivatives as 67, which were evaluated against influenza A and B virus sialidases and used in a viral-replication assay.82 While these molecules displayed similar efficacy to the parent triol against influenza A virus sialidase, they were relatively ineffective against influenza B virus. 

FIGURE 17.6 X-ray structures of influenza virus sialidases. (a) Structure of influenza B virus sialidase tetramer (PDB 1 a4g) viewed from the top [62]. (b) Structure of influenza A virus sialidase N9 monomer (PDB lmwe) with a-Neu5Ac (shown as spheres) bound in the active site [63]. 

Oseltamivir and zanamivir are neuraminidase inhibitors that have activity against both influenza A and influenza B viruses. When administered within 48 hours of the onset of illness, oseltamivir and zanamivir may reduce the duration of illness by approximately 1 day versus placebo. Oseltamivir is approved for treatment in those older than the age of 1 year, while zanamivir is approved for treatment in those older than the age of 7 years. The recommended dosages vary by agent and age (see Table 41-3), and the recommended duration of treatment for both agents is 5 days. The FDA has received 103 reports, occurring between August 29,2005, and July 6,2006, of delirium, hallucinations, and self-injury in pediatric patients (mostly from Japan) following treatment with oseltamivir. 

Amantadine is effective only against influenza A it acts by interfering with the uncoating and release of viral genome into the host cell. It is well absorbed from the gastrointestinal tract and is eliminated in the mine 3 h). Amantadine may be used orally for the prevention and treatment of infection with influenza A (but not influenza B) virus. Those most likely to benefit include the debilitated, persons with respiratory disability and people living in crowded conditions, especially during an influenza epidemic. 

Amantadine is a symmetrical CIO tricyclic amine with an unusual structure (1-adamantanamine hydrochloride). It interferes with virus uncoating (1) by blocking the M2 ion channel, which is needed to affect a pH change that helps to initiate the uncoating process. Most consistent antiviral activity has been observed against influenza A virus, but amantadine has httle or no activity against influenza B virus (2). However, influenza A virus can become rapidly resistant to amantadine in vitro (3). Amantadine also promotes the release of dopamine from nerve endings, but may also delay its reuptake into synaptic vesicles. 

Clinical use of these drugs is limited not just because of their ineffectiveness against influenza B viruses, but also because of the rapid emergence of resistance [40]. A new class of agents, the neuraminidase inhibitors, has recently been developed that possesses significant activity against both influenza A and B strains. 

Based on the lead compound BANA 113 42, which inhibits influenza A neuraminidase with a Ki of 2.5 p.M [91a,b], several novel 2-pyrrolidinone derivatives were designed. Whereas compound 43 (BANA 205) is a relatively weak inhibitor of influenza A and B neuraminidases, with IC50 values in the low micromolar range, compound 44 (BANA 206) is much more potent, with an IC50 value of 48 nM against influenza A neuraminidase. However, this compound is not as potent against influenza B virus sialidase [91d,e]. 

G. Xu, T. Suzuki, H. Tahara, M. Kiso, A. Hasegawa, and Y. Suzuki, Specificity of sialyl-sugar chain mediated recognition by the hemagglutinin of human influenza B virus isolates, J. Biochem. (Tokyo) 115 202 (1994), and references therein. 

Note Influenza surveillance this year in the area shows a predominance of influenza B virus. 

Which agents are active against influenza B virus ... 

Amantadine and rimantadine are chemically related antiviral drugs active against influenza A but not influenza B viruses. Amantadine differs from rimantadine because it is primarily renally eliminated and is associated with more CNS side effects and can potentially lower the seizure threshold. 

The drug amantadine and its analogue rimantidine are the only compounds licensed for the prophylaxis and treatment of influenza A infection. These compounds act blocking the ion channel function of the virus protein M2 [14,15], but they may account for the lack of activity against influenza B viruses, which do not possess this protein. 

Hart, G. J. and Bethell, R. C. (1995) 2,3-Didehydro-2,4-dideoxy-4-guanidino-N-acetylneuraminic acid (4-guanindino-Neu5Ac2en) is a slow-binding inhibitor of sialidase from both influenza A and influenza B virus. Biochem. Mol. Biol. Int. 36, 695-703. 

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