TY - JOUR

T1 - Impact of Delivery Method on Antiviral Activity of Phosphodiester, Phosphorothioate, and Phosphoryl Guanidine Oligonucleotides in MDCK Cells Infected with H5N1 Bird Flu Virus

AU - Levina, A. S.

AU - Repkova, M. N.

AU - Chelobanov, B. P.

AU - Bessudnova, E. V.

AU - Mazurkova, N. A.

AU - Stetsenko, D. A.

AU - Zarytova, V. F.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - We have previously described nanocomposites containing conjugates or complexes of native oligodeoxyribonucleotides with poly-L-lysine and TiO2 nanoparticles. We have shown that these nanocomposites efficiently suppressed influenza A virus reproduction in MDCK cells. Here, we have synthesized previously undescribed nanocomposites that consist of TiO2 nanoparticles and polylysine conjugates with oligonucleotides that contain phosphoryl guanidine or phosphorothioate internucleotide groups. These nanocomposites have been shown to exhibit antiviral activity in MDCK cells infected with H5N1 influenza A virus. The nanocomposites containing phosphorothioate oligonucleotides inhibited virus replication ~130-fold. More potent inhibition, i.e., ~5000-fold or ~4600-fold, has been demonstrated by nanocomposites that contain phosphoryl guanidine or phosphodiester oligonucleotides, respectively. Free oligonucleotides have been nearly inactive. The antiviral activity of oligonucleotides of all three types, when delivered by Lipofectamine, has been significantly lower compared to the oligonucleotides delivered in the nanocomposites. In the former case, the phosphoryl guanidine oligonucleotide has appeared to be the most efficient; it has inhibited the virus replication by a factor of 400. The results make it possible to consider phosphoryl guanidine oligonucleotides, along with other oligonucleotide derivatives, as potential antiviral agents against H5N1 avian flu virus.

AB - We have previously described nanocomposites containing conjugates or complexes of native oligodeoxyribonucleotides with poly-L-lysine and TiO2 nanoparticles. We have shown that these nanocomposites efficiently suppressed influenza A virus reproduction in MDCK cells. Here, we have synthesized previously undescribed nanocomposites that consist of TiO2 nanoparticles and polylysine conjugates with oligonucleotides that contain phosphoryl guanidine or phosphorothioate internucleotide groups. These nanocomposites have been shown to exhibit antiviral activity in MDCK cells infected with H5N1 influenza A virus. The nanocomposites containing phosphorothioate oligonucleotides inhibited virus replication ~130-fold. More potent inhibition, i.e., ~5000-fold or ~4600-fold, has been demonstrated by nanocomposites that contain phosphoryl guanidine or phosphodiester oligonucleotides, respectively. Free oligonucleotides have been nearly inactive. The antiviral activity of oligonucleotides of all three types, when delivered by Lipofectamine, has been significantly lower compared to the oligonucleotides delivered in the nanocomposites. In the former case, the phosphoryl guanidine oligonucleotide has appeared to be the most efficient; it has inhibited the virus replication by a factor of 400. The results make it possible to consider phosphoryl guanidine oligonucleotides, along with other oligonucleotide derivatives, as potential antiviral agents against H5N1 avian flu virus.

KW - conjugates

KW - influenza A virus

KW - inhibitors

KW - nanoparticles

KW - oligonucleotides

KW - replication

KW - Animals

KW - Antiviral Agents/chemical synthesis

KW - Dogs

KW - Dose-Response Relationship, Drug

KW - Drug Carriers

KW - Guanidines/chemistry

KW - Influenza A Virus, H5N1 Subtype/drug effects

KW - Lipids/chemistry

KW - Madin Darby Canine Kidney Cells

KW - Nanocomposites/chemistry

KW - Oligonucleotides/chemistry

KW - Organophosphates/chemistry

KW - Phosphorothioate Oligonucleotides/chemistry

KW - Polylysine/chemistry

KW - Titanium/chemistry

KW - Virus Replication/drug effects

UR - http://www.scopus.com/inward/record.url?scp=85044180773&partnerID=8YFLogxK

U2 - 10.7868/S0026898417040139

DO - 10.7868/S0026898417040139

M3 - Article

C2 - 28900092

AN - SCOPUS:85044180773

VL - 51

SP - 717

EP - 723

JO - Molekulyarnaya Biologiya

JF - Molekulyarnaya Biologiya

SN - 0026-8984

IS - 4

ER -