Inhibition of Influenza a Virus Replication by Antagonism of a PI3K-AKT-mTOR Pathway Member Identified by Gene-Trap Insertional Mutagenesis

Murray, James L.; McDonald, Natalie J.; Sheng, Jinsong; Shaw, Michael; Hodge, Thomas; Rubin, Donald H.; O’Brien, William A.; Smee, Donald F.

doi:10.3851/imp2080

Cited by 58 publications

(64 citation statements)

References 42 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A/Solomon Islands/3/2006 (H1N1) became lethal to mice after seven serial passages in the lungs of infected animals (Murray et al, 2012). To confirm that the mouse-adapted A/Solomon Islands/3/2006 (H1N1) virus was sensitive to amantadine ( 1 ) and compound 3 , plaque assays were performed.…”

Section: Resultsmentioning

confidence: 99%

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

Musharrafieh

et al. 2017

Antiviral Research

View full text Add to dashboard Cite

Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors. One of the potent lead compounds, spiroadamantane amine (3), inhibits both the M2-WT and M2-V27A mutant with IC50 values of 18.7 and 0.3 μM, respectively, in in vitro electrophysiological assays. Encouraged by these findings, in this study we further examine the in vitro and in vivo antiviral activity of compound 3 in inhibiting both amantadine-sensitive and -resistant influenza A viruses. Compound 3 not only had single to submicromolar EC50 values against M2-WT- and M2-V27A-containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses. In addition, we report the design of two analogs of compound 3, and one was found to have improved in vitro antiviral activity over compound 3. Collectively, this study represents the first report demonstrating the in vivo antiviral efficacy of inhibitors targeting M2 mutants. The results suggest that inhibitors targeting drug-resistant M2 mutants are promising antiviral drug candidates worthy of further development.

show abstract

Section: Resultsmentioning

confidence: 99%

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

Musharrafieh

et al. 2017

Antiviral Research

View full text Add to dashboard Cite

show abstract

“…The results with mTOR inhibitors remain ambiguous. Everolimus therapy improved the outcome with a delay of 1.8 days in death and a marginal survival benefit beyond 14 days post-infection in an animal model 20 . There has been a reported success in human H1N1 virus infection with adjuvant Rapamycin in addition to standard Oseltamivir treatment 21 .…”

Section: Introductionmentioning

confidence: 93%

Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model

Huang

Hung

Chen

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Influenza virus infection often causes severe disease and acute respiratory distress syndrome. It is a common belief that overwhelming immune response contributes to the severe illness. Physicians and researchers have put forth immune modulation as salvage therapy for better recovery. However, empiric corticosteroid failed in both humans and animal models. Reported success with Rapamycin in humans prompted a comprehensive animal study and mechanistic dissection. Here we report the effect of Rapamycin alone or in combination with Oseltamivir for severe influenza in BALB/c mice. We found that Rapamycin had no antiviral effect against H1N1, H3N2 and novel-H1N1 influenza viruses in vitro. Rapamycin alone aggravated the severe disease of PR8 H1N1 influenza virus infection in mice. Timely Oseltamivir anti-viral therapy abolished the disease. Delayed Oseltamivir treatment could not prevent severe illness and Rapamycin adjuvant was associated with exacerbated disease. Rapamycin adjuvant suppressed influenza hemagglutinin antigen-specific T cell immunity and impaired virus clearance from the lungs. It also resulted in intensified lung pathology with increased intra-alveolar edema and hyaline deposition. Rapamycin may work as the salvage therapy for severe influenza but it is very difficult to define the appropriate window for such treatment to take effect.

show abstract

“…In particular, Akt signaling is involved in influenza virus uptake as well as at the later stages of the virus replication cycle (11)(12)(13)(14). Here, we tested MK2206, an Akt inhibitor, against different influenza virus infections and showed that MK2206 has anti-pH1N1 activity in vitro.…”

mentioning

confidence: 99%

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Denisova

Söderholm

Virtanen

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The influenza pH1N1 virus caused a global flu pandemic in 2009 and continues manifestation as a seasonal virus. Better understanding of the virus-host cell interaction could result in development of better prevention and treatment options. Here we show that the Akt inhibitor MK2206 blocks influenza pH1N1 virus infection in vitro. In particular, at noncytotoxic concentrations, MK2206 alters Akt signaling and inhibits endocytic uptake of the virus. Interestingly, MK2206 is unable to inhibit H3N2, H7N9, and H5N1 viruses, indicating that pH1N1 evolved specific requirements for efficient infection. Thus, Akt signaling could be exploited further for development of better therapeutics against pH1N1 virus.

show abstract

Inhibition of Influenza a Virus Replication by Antagonism of a PI3K-AKT-mTOR Pathway Member Identified by Gene-Trap Insertional Mutagenesis

Cited by 58 publications

References 42 publications

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

An M2-V27A channel blocker demonstrates potent in vitro and in vivo antiviral activities against amantadine-sensitive and -resistant influenza A viruses

Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model

Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection In Vitro

Contact Info

Product

Resources

About