Delivery System Targeting Hemagglutinin of Influenza Virus A to Facilitate Antisense-Based Anti-H1N1 Therapy

5 years ago

Delivery System Targeting Hemagglutinin of Influenza Virus A to Facilitate Antisense-Based Anti-H1N1 Therapy

Zhe Zhou, Qing Jun Li, Zhao Yan Zhang, Jing Yang, Xiao Ran Ding, Dan Dan Lu, Sheng Qi Wang

Antisense oligonucleotides (ODNs) are therapeutic molecules that hybridize to complementary target mRNA sequences. To further overcome the poor cellular uptake of ODNs, we proposed a novel strategy to deliver ODNs by conjugating the anti-influenza A virus (IAV) ODN with a peptide showing high affinity to the hemagglutinin (HA) on the surface of IAV particles or the IAV-infected host cells. The HA-specific binding peptides were selected by phage display, and the individual binding clones are characterized by DNA sequencing, and the selected phage was further assayed by enzyme-linked immunosorbent assay. The final selected HA-binding peptide, SHGRITFAYFAN, was conjugated to an anti-IAV ODN. The delivery efficiency and the anti-IAV effects of the conjugated molecule were evaluated in a cell-culture and a mouse-infection model. The conjugated molecule was successfully delivered into IAV-infected host cells more efficiently than the anti-IAV ODN in vitro and in vivo. Furthermore, the conjugated molecule protected 80% of the mice from lethal challenge and inhibited the plaque count by 75% compared to the unconjugated molecule (60% and 40%). These findings demonstrate that the delivery of antisense oligodeoxynucleotides to infected tissues by a virus-binding peptide-mediated system is a potential therapeutic strategy against IAV.

Publisher URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00124

DOI: 10.1021/acs.bioconjchem.7b00124