Influenza chemotherapy: a review of the present state of art and of new drugs in development

Lüscher-Mattli, Madeleine

doi:10.1007/s007050070017

Cited by 30 publications

(24 citation statements)

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“…Once an individual is infected with influenza, therapeutic options are limited to supportive care or a handful of medications that target viral pathways, primarily neuraminidase (Luscher-Mattli, 2000; Ong and Hayden, 2007). However, the wide application of traditional antiviral medications has favored the emergence of drug-resistant viruses, thereby presenting a major new challenge to the control of infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

The use of Random Homozygous Gene Perturbation to identify novel host-oriented targets for influenza

Sui¹,

Bamba²,

Weng³

et al. 2009

Virology

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Conventional approaches for therapeutic targeting of viral pathogens have consistently faced obstacles arising from the development of resistant strains and a lack of broad-spectrum application. Influenza represents a particularly problematic therapeutic challenge since high viral mutation rates have often confounded many conventional antivirals. Newly emerging or engineered strains of influenza represent an even greater threat as typified by recent interest in avian subtypes of influenza. Based on the limitations associated with targeting virally-encoded molecules, we have taken an orthogonal approach of targeting host pathways in a manner that prevents viral propagation or spares the host from virus-mediated pathogenicity. To this end, we report herein the application of an improved technology for target discovery, Random Homozygous Gene Perturbation (RHGP), to identify host-oriented targets that are well-tolerated in normal cells but that prevent influenza-mediated killing of host cells. Improvements in RHGP facilitated a thorough screening of the entire genome, both for overexpression or loss of expression, to identify targets that render host cells resistant to influenza infection. We identify a set of host-oriented targets that prevent influenza killing of host cells and validate these targets using multiple approaches. These studies provide further support for a new paradigm to combat viral disease and demonstrate the power of RHGP to identify novel targets and mechanisms.

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Section: Introductionmentioning

confidence: 99%

The use of Random Homozygous Gene Perturbation to identify novel host-oriented targets for influenza

Sui¹,

Bamba²,

Weng³

et al. 2009

Virology

View full text Add to dashboard Cite

show abstract

“…In addition, the existing vaccines have to be reformulated almost every year because the viral antigens [hemagglutinin (HA) and neuraminidase (NA)] that elicit protective antibodies usually undergo changes, rendering the previous year's vaccine ineffective against any new virus subtype. Similarly, although four antiviral drugs have been approved in the United States for treatment and͞or prophylaxis of influenza, their use is limited because of severe side effects and the possible emergence of resistant viruses (9).…”

mentioning

confidence: 99%

RNA interference of influenza virus production by directly targeting mRNA for degradation and indirectly inhibiting all viral RNA transcription

McManus

Nguyen

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

482

393

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Influenza A virus causes widespread infection in the human respiratory tract, but existing vaccines and drug therapy are of limited value. Here we show that short interfering RNAs (siRNAs) specific for conserved regions of the viral genome can potently inhibit influenza virus production in both cell lines and embryonated chicken eggs. The inhibition depends on the presence of a functional antisense strand in the siRNA duplex, suggesting that viral mRNA is the target of RNA interference. However, siRNA specific for nucleocapsid (NP) or a component of the RNA transcriptase (PA) abolished the accumulation of not only the corresponding mRNA but also virion RNA and its complementary RNA. These siRNAs also broadly inhibited the accumulation of other viral, but not cellular, RNAs. The findings reveal that newly synthesized NP and PA proteins are required for influenza virus transcription and replication and provide a basis for the development of siRNAs as prophylaxis and therapy for influenza infection in humans.

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“…Many human and avian virus strains have become resistant to conventional influenza antiviral drugs. [43][44][45][46][47][48][49][50] The fact that seemingly unrelated viruses, such as HIV and Ebola viruses, utilize TSG101 in a manner analogous to our present findings with influenza suggests that these viruses have not evolved alternative mechanisms to facilitate viral budding. This raises an intriguing question of whether TSG101-independent viral variants could arise.…”

mentioning

confidence: 65%

Antibody targeting of TSG101 on influenza-infected cells

Kinch¹

2010

VAAT

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Influenza remains a significant cause of morbidity and mortality worldwide. Although vaccination programs and conventional antiviral therapies can reduce disease burden, increasing resistance to conventional therapies renders much of the population susceptible to infection. The present study focuses on an important host protein target, tumor susceptibility gene 101 (TSG101), which is functionally exploited (hijacked) by certain enveloped viruses to facilitate viral budding and release. We find that influenza viruses depend on TSG101 for progeny virion morphogenesis in infected host cells. Antibody-binding studies revealed that TSG101 is exposed at the surface of influenza-infected cells but remains intracellular in uninfected cells. Using recombinant TSG101 and influenza M1 protein, we demonstrated a direct interaction between these proteins involving the ubiquitin E2 variant domain of TSG101. These findings identify an interaction between TSG101 and M1 protein in infected cells. Furthermore, a monoclonal antibody directed against TSG101 reduced virus yields in cell-based assessment of influenza virus infection, underscoring the potential of the TSG101-M1 interaction as a possible antiviral therapeutic target. The display of TSG101 at the surface of infected cells, combined with evidence that TSG101 antibodies reduce virus yields, suggest that TSG101 plays an essential role in the budding process of influenza virus. Our findings may also suggest potential opportunities for influenza treatment and prevention by using monoclonal antibody therapeutics to interfere with virus replication.

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Influenza chemotherapy: a review of the present state of art and of new drugs in development

Cited by 30 publications

References 0 publications

The use of Random Homozygous Gene Perturbation to identify novel host-oriented targets for influenza

The use of Random Homozygous Gene Perturbation to identify novel host-oriented targets for influenza

RNA interference of influenza virus production by directly targeting mRNA for degradation and indirectly inhibiting all viral RNA transcription

Antibody targeting of TSG101 on influenza-infected cells

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