Anti-Influenza A Synergistic Combination Effect of Rimantadine and Oseltamivir in Mice

Simeonova, Lora; Galabov, Angel S.; Gegova, G

doi:10.1016/j.antiviral.2007.01.055

Cited by 2 publications

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“…The need for combination therapy is further justified because monotherapy with oseltamivir was suboptimal in the treatment of H5N1-infected patients, with a mortality rate as high as 60% (Abdel-Ghafar et al, 2008;Kandun et al, 2008). It has been shown in a number of studies that a combination of M2 inhibitors (amantadine or rimantadine) with neuraminidase inhibitors (oseltamivir carboxylate or peramivir), ribavirin, or a combination of all three was in general synergistic in in vitro cell culture assays and in vivo mouse studies (Govorkova et al, 2004;Ilyushina et al, 2006Ilyushina et al, , 2007Simeonova et al, 2007Simeonova et al, , 2008Simeonova et al, , 2009Smee et al, 2009;Bantia et al, 2010). Gratifyingly, our rationally designed M2-S31N inhibitor WJ379 displayed strong synergy with oseltamivir carboxylate, with a synergy volume of 166, suggesting that combination therapy of WJ379 with oseltamivir carboxylate might be an option for controlling influenza viruses in the future.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of the Spectrum of Antiviral Activity and Genetic Barrier to Drug Resistance of M2-S31N Channel Blockers

Zhang

Wang

2016

Mol Pharmacol

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Adamantanes (amantadine and rimantadine) are one of the two classes of Food and Drug Administration-approved antiviral drugs used for the prevention and treatment of influenza A virus infections. They inhibit viral replication by blocking the wild-type (WT) M2 proton channel, thus preventing viral uncoating. However, their use was discontinued due to widespread drug resistance. Among a handful of drug-resistant mutants, M2-S31N is the predominant mutation and persists in more than 95% of currently circulating influenza A strains. We recently designed two classes of M2-S31N inhibitors, S31N-specific inhibitors and S31N/WT dual inhibitors, which are represented by N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]adamantan-1-amine (WJ379) and N-[(5-bromothiophen-2-yl)methyl]adamantan-1-amine (BC035), respectively. However, their antiviral activities against currently circulating influenza A viruses and their genetic barrier to drug resistance are unknown. In this report, we evaluated the therapeutic potential of these two classes of M2-S31N inhibitors (WJ379 and BC035) by profiling their antiviral efficacy against multidrug-resistant influenza A viruses, in vitro drug resistance barrier, and synergistic effect with oseltamivir. We found that M2-S31N inhibitors were active against several influenza A viruses that are resistant to one or both classes of Food and Drug Administration-approved anti-influenza drugs. In addition, M2-S31N inhibitors display a higher in vitro genetic barrier to drug resistance than amantadine. The antiviral effect of WJ379 was also synergistic with oseltamivir carboxylate. Overall, these results reaffirm that M2-S31N inhibitors are promising antiviral drug candidates that warrant further development.

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