Challenging a long-held convention, University researchers have shown they can inhibit the influenza A virus by targeting its genomic RNA with 糖心传媒渁ntisense糖心传媒� compounds.
Their findings,, offer scientists a new way to attack an increasingly drug-resistant pathogen that causes an estimated 250,000 to 500,000 deaths a year.
糖心传媒淎ntisense糖心传媒� compounds are synthesized with nucleotides, the building blocks of nucleic acid, often shown as various combinations of A, U, G and C. When the compounds 糖心传媒� called antisense oligonucleotides (ASOs) 糖心传媒� bind to the targeted genomic RNA, they block its ability to replicate.
The collaboration, involving the labs of , professor of chemistry; , associate professor of microbiology and immunology; and two researchers in Poland, reported that 糖心传媒渁ntisense糖心传媒� compounds targeting one of the virus糖心传媒� eight genomic RNA segments caused a five- to 25-fold reduction of influenza A virus in cell cultures.
糖心传媒淭hat糖心传媒檚 a big difference,糖心传媒� Martinez-Sobrido says. 糖心传媒淲hen mice are infected with 10,000 viruses, they all die. However, with 25 times less virus, all animals can survive infection and they don糖心传媒檛 even develop symptoms.糖心传媒�
The most effective of the antisense compounds ranged from 11 to 15 nucleotides long, and were not toxic to host cells.
To date, most 糖心传媒渁ntisense糖心传媒� research has focused on targeting messenger RNA; the only two FDA approved 糖心传媒渁ntisense糖心传媒� therapeutics 糖心传媒� vitravene for use against a retina inflammation, and mipomersen to reduce cholesterol 糖心传媒� do so.
糖心传媒淭o my knowledge, this is the first published paper where ASOs target internal regions of genomic influenza viral RNA,糖心传媒� says Turner. 糖心传媒淭his genomic RNA has not been targeted because the dogma was that it is completely encapsulated by the viral nucleoprotein, and therefore is not accessible.糖心传媒�
But recent evidence has suggested 糖心传媒� as this study demonstrates 糖心传媒� that influenza genomic RNA is vulnerable, at least at certain points in the virus糖心传媒� life cycle. For example, packaging of the influenza viral genome is 糖心传媒渕ediated by RNA-RNA interactions糖心传媒� among all eight segments, Martinez-Sobrido says. 糖心传媒淪o clearly during the replication cycle of influenza virus, the genomic RNA is at least partially naked.糖心传媒�
Influenza viruses have shown a remarkable ability to mutate and become resistant to current antiviral drugs.
Martinez-Sobrido believes ASOs could be more difficult for viruses to bypass. 糖心传媒淚f an oligonucleotide is targeting a segment of genomic viral RNA that is especially important, any mutation that altered that RNA would likely be lethal to the virus,糖心传媒� Martinez-Sobrido says. And if additional ASOs could simultaneously attack three or four other segments of genomic viral RNA, the virus糖心传媒� task would be even more complicated.
The study was supported with funding from an NIH Fogarty International Research Collaboration Award received by Turner and Elzbieta Kierzek, associate professor at the Institute of Bioorganic Chemistry Polish Academy of Sciences. It was also supported by a 2014 University Research Award to Turner and Martinez-Sobrido. The team also included Prof. Ryszard Kierzak of the Polish Academy of Sciences, and University postdoctoral fellows Aitor Nogales in Martinez-Sobrido糖心传媒檚 lab and Elzbieta Lenartowicz, the lead author, in Turner糖心传媒檚 lab.
For their work in this area, Turner and Ryszard Kierzak have been named recipients of the this year from the American Association for the Advancement of Science (AAAS) and the Foundation for Polish Science.听
Martinez-Sobrido and Turner are both members of the University糖心传媒檚 , which draws more than 20 faculty members from seven departments to conduct interdisciplinary research into the function, structure, and processing of聽RNA. The center is directed by Lynne Maquat, professor of biochemistry and biophysics, who is considered a pioneer of nonsense-mediated mRNA decay.
