The patent's inventors are Niazi, Kayvan (
This patent was filed on
From the background information supplied by the inventors, news correspondents obtained the following quote: "Influenza A virus is a member of the orthomyxoviridae virus family of (-)-sense RNA viruses. The influenza A viral genome is composed of 8 segments or chromosomes which encode 11 proteins.sup.1. During infection, the virus-encoded RNA-dependent RNA polymerase (RdRP) converts the (-)-stranded RNAs to (+) strand messenger RNAs and a set of full length complementary genomic RNAs (or cRNAs) which serve as templates for genomic replication. Viral proteins expressed from the (+) strand messenger RNAs go about the task of establishing infection and facilitating viral replication, a process which ends in the amplification, assembly, and release of virus particles containing the initial 8 (-) strand chromosomes which repeat the infectious cycle.
"The processes associated with the transcription and replication of the influenza A genome have been under investigation for decades. All eight chromosomes of every influenza A strain (including H1N1 seasonal, H1N1 'swine', H3N2, and H5N1 'avian') contain identical 5' and nearly identical 3' untranslated regions (UTRs) flanking the protein-coding portion of the sequence which otherwise encode distinct proteins. Experimental results demonstrate that the UTRs are recognized by RdRP as a promoter element and both components are critical for viral gene expression and replication. Hence, the viral polymerase and its cognate UTR RNA ligand are thought to control the viral life cycle and are critical targets for therapeutic intervention.
"Despite such relatively detailed knowledge of viral replication, currently existing and clinically approved anti-influenza A therapeutic molecules are restricted to small molecules that inhibit one of two target classes of viral coat proteins: Neuraminidase (NA) and Matrix 2 (M2). NA belongs to a broad class of glycoside hydrolase enzymes (also known as sialidases, as N- or O-linked neuraminic acids are collectively called sialic acid) which cleave terminal sialic acid residues off virions and host cell receptor proteins. During influenza A infection, NA activity is involved in viral transit through mucus secretions of the respiratory tract as well as for the biochemical separation/elution of secreted viruses from the infected cells serving as sites of replication, thereby enabling the infection of nearby healthy cells. Currently, oseltamivir (trade name Tamiflu.RTM.) and zanamivir (trade name Relenza.RTM.) are two clinically approved medications for the treatment of influenza infection through inhibition of NA while laninamivir (Inavir) and peramivir are currently in the late stages of clinical trials as next-generation influenza NA inhibitors.
"NA and M2 inhibitors serve as successful proof-of-concept small molecule inhibitors of critical steps in the influenza virus infection cycle. Despite their early successes, however, use of both NA and M2 inhibitors has met recent challenges in treating influenza infection through the emergence of viral variants exhibiting drug resistance. For example, evidence of viral resistance to Tamiflu has been documented in numerous clinically relevant influenza A isolates including the 2009 pandemic.sup.5, H3N2.sup.6, H5N1.sup.7, and seasonal H1N1.sup.8 where resistance existed in 99.6% of circulating isolates in 2008. Although influenza A resistance to zanamivir has yet to be reported, the report of an influenza B viral isolate resistant to this agent.sup.9 may indicate the possibility of future more prevalent resistance to this drug upon broad usage to treat influenza infections although the resistant virus described in this study had acquired an additional compensatory mutation in the HA protein which should reduce this possibility significantly. With regards to the M2 inhibitors, the
"Unfortunately, surveillance efforts have also identified the recent emergence of dual oseltamivir/adamantane resistant isolates.sup.11 indicating the need for the discovery and utilization of additional small molecule inhibitors targeting other critical viral targets. Thus, there is still a need to provide new and/or improved antiviral drugs that interfere with viral replication, and especially RNA-virus replication."
Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "The inventors have discovered various compositions and methods that interfere with the infectious life cycle of influenza A, and most likely with viral replication. Moreover, the inventors have also discovered components and methods for a cellular assay to identify small molecule compounds having antiviral properties. In especially preferred aspects, the assay allows for detection of influenza A RNA-dependent RNA polymerase activity in a mammalian cell independent of other influenza A components, and allows for identification of inhibitors of viral replication that do not disrupt normal cellular activity.
"In another aspect of the inventive subject matter, selected compounds are provided with antiviral properties. Particularly preferred compounds (A0435) were evaluated in an in vitro viral propagation system utilizing three different influenza A strains representing two different serotypes of virus and found to inhibit all three viruses at low .mu.M concentrations and to prevent host cells from displaying virus-induced cytopathic effects (CPE). Consistent with these results, certain compounds, and especially A0435, also demonstrated antiviral activity in a live infection mammalian model of influenza A.
"Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention."
For the URL and additional information on this patent, see: Niazi, Kayvan; Rabizadeh, Shahrooz;
Keywords for this news article include: Viruses, Peptides, Proteins, Virology, Influenza, Viral RNA, Polymerase, Amino Acids, Chromosomes, Cell Nucleus, Intranuclear Space, Cellular Structures, Intracellular Space,
Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC
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