Inhibition of influenza A virus reproduction by a ribozyme targeted against PB1 mRNA

Лазарев, В. Н.; Шмаров, М. М.; Zakhartchouk, Alexandre N.; Yurov, Gleb K.; Misurina, O U; Akopian, T. A.; Grinenko, N. F.; Grodnitskaya, N G; Каверин, Н. В.; Naroditsky, Boris S.

doi:10.1016/s0166-3542(99)00015-7

Cited by 18 publications

(11 citation statements)

References 20 publications

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“…Since present vaccines and drug therapy are of limited value in influenza prevention, RNA targeting nucleic medicines such as ribozyme and siRNA 17,18) have been developed for the influenza virus. however, these nucleic acid medicines have not been established as standard therapies.…”

Section: Discussionmentioning

confidence: 99%

RNA Binding Properties of Novel Gene Silencing Pyrrole-Imidazole Polyamides

Iguchi

Fukuda

Takahashi

et al. 2013

Biological & Pharmaceutical Bulletin

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Pyrrole-imidazole (PI) polyamides are a novel group of gene-silencing compounds, which bind to a minor groove of double stranded (ds)DNA in a sequence-specific manner. To explore the RNA binding properties of PI polyamides targeting rat transforming growth factor-β1 (TGF-β1 Polyamide) and influenza A virus (PA polyamide), we designed dsRNAs with an identical sequence to the target DNA and analyzed RNA binding properties of the polyamide. Biacore assay showed fast binding of TGF-β1 Polyamide to the dsRNA, whereas mismatch polyamide did not bind to the dsRNA. Dissociation equilibrium constant (KD) value was 6.7×10 −7 of the target dsRNA. These results indicate that PI polyamide could bind to RNA with a 2 log lower binding affinity than its DNA-binding affinity. We designed a PI polyamide targeting the panhandle stem region of influenza A virus. KD value of the PI polyamide to dsRNA targeting influenza A virus was 4.6×10 −7. Gel-shift assay showed that TGF-β1 and PA polyamides bound to the appropriate dsDNA, whereas these PI polyamides did not show obvious gel-shift with the appropriate dsRNA. Structural modeling suggests that PI polyamide binds to the appropriate B-form dsDNA in the minor groove, whereas it does not fit in the minor groove to dsRNA. Thus PI polyamides have a lower binding affinity with target dsRNA than they do with dsDNA. The distinct binding properties of PI polyamides to dsRNA and dsDNA may be associated with differences of secondary structure and chemical binding properties between target RNA and DNA.Key words pyrrole-imidazole polyamide; double-stranded RNA; affinity; Biacore; gel-shift assay; influenza virus Engineered inactivation of gene function is important for elucidating the function of particular genes and may be used in gene therapy, treatment of viral infection, cancer and other diseases caused by aberrant gene expression. Gene function can be inactivated at the DNA level by nucleic acid medicines such as anti-gene 1) or antisense peptide nucleic acid, or at the RNA level by antisense oligodeoxynucleotides, 2) ribozymes, 3) small interfering RNA (siRNA), 4) and aptamers. 5)Since these nucleic acid agents are easily degraded by nucleases, suitable chemical modifications or drug-delivery systems, including vectors, are required for their therapeutic applications. Transcriptional regulation is essential for gene expression. Initiation of transcription requires binding of transcription factors to the cognate DNA response elements in the gene promoter. Thus, we developed pyrrole-imidazole (PI) polyamides as a novel gene-suppressing agent. PI polyamides were first identified from duocarmycin A and distamycin A and are small synthetic molecules that are composed of the aromatic rings of N-methylpyrrole and N-methylimidazole amino acids. 6) Synthetic PI polyamides can bind to specific nucleotide sequences in the minor groove of double-stranded (ds) DNA with high affinity and specificity. PI polyamides are completely resistant to nucleases and could be delivered into tissues without any drug...

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Section: Discussionmentioning

confidence: 99%

RNA Binding Properties of Novel Gene Silencing Pyrrole-Imidazole Polyamides

Iguchi

Fukuda

Takahashi

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Hammerhead Rz have been reported to be more efficient at the target site than the hairpin Rz. Rzs have also been designed against the mRNA coding for PB1 protein of influenza and has shown suppression of virus reproduction [49]. The hepatitis delta virus Rz (HDV-Rz), derived from HDV can specifically recognize and catalyze the cleavage of target RNA molecules.…”

Section: • • Ribozymes and Dnazymesmentioning

confidence: 99%

“…Various research groups have worked on developing different mechanisms for efficient delivery of siRNAs to the target cells/tissues (Table 1). These include physical methods, conjugation method [46,47] electroporation [54], lipid-based carriers [49][50][51][52][53][54][55][56][57] cationic polymers [33, [57][58][59][60][61][62].…”

Section: • • Ribozymes and Dnazymesmentioning

confidence: 99%

Gene Silencing: A Therapeutic Approach to Combat Influenza Virus Infections

et al. 2015

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Selective gene silencing technologies such as RNA interference (RNAi) and nucleic acid enzymes have shown therapeutic potential for treating viral infections. Influenza virus is one of the major public health concerns around the world and its management is challenging due to a rapid increase in antiviral resistance. Influenza vaccine also has its limitations due to the emergence of new strains that may escape the immunity developed by the previous year's vaccine. Antiviral drugs are the primary mode of prevention and control against a pandemic and there is an urgency to develop novel antiviral strategies against influenza virus. In this review, we discuss the potential utility of several gene silencing mechanisms and their prophylactic and therapeutic potential against the influenza virus.

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“…This strategy also holds the promise to overcome the virus mutagenesis problem by simultaneously targeting a number of viral RNA genes and transcripts. In addition to the application in influenza A virus [108], hepatitis viruses [109][110][111], and human cytomegalovirus [112,113], ribozymes are mainly used to fight HIV infection at a variety of points in the HIV infectious cycle, such as prior to genomic viral RNA into the target cell, prior to translation of mRNAs to viral proteins, and prior to genomic RNA encapsulation during virus assembling. Successful examples include a 5′U5 leadertargeting ribozyme protecting T cell lines from HIV-1 infection [114], and ribozymes cleaving tat and rev RNAs of HIV [115,116] and providing an effective long-term protection against HIV-1 infection in a SCID-hu mouse model of in vivo thymopoiesis.…”

Section: Ribozymesmentioning

confidence: 99%

Chemical and structural biology of nucleic acids and protein-nucleic acid complexes for novel drug discovery

2011

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Since nucleic acids (DNA and RNA) play very important roles in cells, they are molecular targets of many clinically used drugs, such as anticancer drugs and antibiotics. Because of clinical demands for treating various deadly cancers and drug-resistant strains of pathogens, there are urgent needs to develop novel therapeutic agents. Targeting nucleic acids hasn't been the mainstream of drug discovery in the past, and the lack of 3D structural information for designing and developing drug specificity is one of the main reasons. Fortunately, many important structures of nucleic acids and their protein complexes have been determined over the past decade, which provide novel platforms for future drug design and discovery. In this review, we describe some useful nucleic acid structures, particularly their interactions with the ligands and therapeutic candidates or even drugs. We summarize important information for designing novel potent drugs and for targeting nucleic acids and protein-nucleic acid complexes to treat cancers and overcome the drug-resistant problems.nucleic acid targets, DNA and RNA, protein-nucleic acid complexes, DNA duplex and junction, G-quadruplex, ribozyme, riboswitch, ribosome, topoisomerase, inhibitors, antibiotics, structure-based drug design, therapeutic agents

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Inhibition of influenza A virus reproduction by a ribozyme targeted against PB1 mRNA

Cited by 18 publications

References 20 publications

RNA Binding Properties of Novel Gene Silencing Pyrrole-Imidazole Polyamides

RNA Binding Properties of Novel Gene Silencing Pyrrole-Imidazole Polyamides

Gene Silencing: A Therapeutic Approach to Combat Influenza Virus Infections

Chemical and structural biology of nucleic acids and protein-nucleic acid complexes for novel drug discovery

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