Re: Antimicrob Agents Chemoter. Activity of the oral neuraminidase inhibitor A-322278 against the oseltamivir-resistant H274Y (A/H1N1) influenza mutant in mice.
hmm, A-322278 ?
pubmed has:
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1: Activity of the oral neuraminidase inhibitor A-322278 against the oseltamivir-resistant H274Y (A/H1N1) influenza mutant in mice.
Baz M, Abed Y, Nehm? B, Boivin G.
Antimicrob Agents Chemother. 2008 Nov 17. [Epub ahead of print]
2: Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes.
Abed Y, Nehm? B, Baz M, Boivin G.
Antiviral Res. 2008 Feb;77(2):163-6. Epub 2007 Sep 10.
3: Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection.
Ison MG, Mishin VP, Braciale TJ, Hayden FG, Gubareva LV.
J Infect Dis. 2006 Mar 15;193(6):765-72. Epub 2006 Feb 13.
PMID: 16479509 [PubMed - indexed for MEDLINE]
4: Susceptibilities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors.
Mishin VP, Hayden FG, Gubareva LV.
Antimicrob Agents Chemother. 2005 Nov;49(11):
J Infect Dis. 2006 Mar 15;193 (6):765-772 16479509 (P,S,G,E,B)
[Cited?]
Comparative Activities of Oseltamivir and A-322278 in Immunocompetent and Immunocompromised Murine Models of Influenza Virus Infection.
[My paper] Michael G Ison, Vasiliy P Mishin, Thomas J Braciale, Frederick G Hayden, Larisa V Gubareva
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, USA. Present affiliation: Transplant Infectious Diseases Service, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
We developed an immunocompromised murine model of influenza virus infection and demonstrated comparable efficacy of oral oseltamivir and A-322278 (both given at dosages of 10 mg/kg/day) in reducing viral replication, decreasing weight loss, and prolonging survival. Once the treatment was discontinued, severe combined immunodeficient (SCID) mice had progressive viral replication and clinical decline. Drug-resistant variants were detected in 4 (29%) of 14 and 2 (13%) of 15 mice (both BALB/c and SCID) treated with oseltamivir or A-322278, respectively; no resistant variants were detected in placebo-treated mice. Amino acid substitutions in the hemagglutinin receptor-binding site at aa 137 or 225 were detected in cloned resistant isolates. A substitution in the neuraminidase (NA) active site (Arg292Lys) was detected in the cloned virus recovered from an oseltamivir-treated mouse. This model would be useful for elucidation of the molecular mechanisms of resistance to NA inhibitors and for testing of anti-influenza therapy options that might prevent the emergence of resistant variants.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16251290
The susceptibilities of five zanamivir-resistant and six oseltamivir-resistant influenza viruses were assessed against four neuraminidase (NA) inhibitors, including peramivir and A-315675, by a fluorometric NA activity inhibition assay. The enzyme activity of a majority of the variants was effectively inhibited by either A-315675 or both peramivir and A-315675 (50% inhibitory concentration, <10 nM). A novel oseltamivir-resistant influenza virus B variant carrying substitution at residue 198 (Asp→Asn) (N2 numbering) retained susceptibility to peramivir and A-315675. In vivo, the Asn198 variant showed no apparent fitness impairment as judged by its recovery on day 5 from the nasal washes of ferrets coinfected with equal doses of the wild-type virus and the Asn198 variant. Based on the sequence analysis of the virus in the nasal washes, oseltamivir treatment (5 mg/kg twice daily for 5 days) did not provide growth advantage to the Asn198 variant. Nevertheless, treatment with A-315675 (prodrug A-322278) reduced the number of the animals (two of seven) shedding the Asn198 variant. These studies indicate that different patterns of susceptibility and cross-resistance between NA inhibitors may prove important if antiviral resistance to zanamivir and oseltamivir were to emerge.
