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Title: A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure
Authors: Kesy, Julita
Patil, Kiran M.
Kumar, Subaschandrabose Rajesh
Shu, Zhiyu
Yong, Hui Yee
Zimmermann, Louis
Ong, Alan Ann Lerk
Toh, Desiree-Faye Kaixin
Krishna, Manchugondanahalli S.
Yang, Lixia
Decout, Jean-Luc
Luo, Dahai
Prabakaran, Mookkan
Chen, Gang
Kierzek, Elzbieta
Keywords: Science::Chemistry
Issue Date: 2019
Source: Kesy, J., Patil, K. M., Kumar, S. R., Shu, Z., Yong, H. Y., Zimmermann, L., Ong, A. A. L., Toh, D. K., Krishna, M. S., Yang, L., Decout, J., Luo, D., Prabakaran, M., Chen, G. & Kierzek, E. (2019). A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure. Bioconjugate Chemistry, 30(3), 931-943.
Project: RGT3/13
Journal: Bioconjugate Chemistry
Abstract: RNAs play critical roles in diverse catalytic and regulatory biological processes and are emerging as important disease biomarkers and therapeutic targets. Thus, developing chemical compounds for targeting any desired RNA structures has great potential in biomedical applications. The viral and cellular RNA sequence and structure databases lay the groundwork for developing RNA-binding chemical ligands through the recognition of both RNA sequence and RNA structure. Influenza A virion consists of eight segments of negative-strand viral RNA (vRNA), all of which contain a highly conserved panhandle duplex structure formed between the first 13 nucleotides at the 5' end and the last 12 nucleotides at the 3' end. Here, we report our binding and cell culture anti-influenza assays of a short 10-mer chemically modified double-stranded RNA (dsRNA)-binding peptide nucleic acid (PNA) designed to bind to the panhandle duplex structure through novel major-groove PNA·RNA2 triplex formation. We demonstrated that incorporation of chemically modified PNA residues thio-pseudoisocytosine (L) and guanidine-modified 5-methyl cytosine (Q) previously developed by us facilitates the sequence-specific recognition of Watson-Crick G-C and C-G pairs, respectively, at physiologically relevant conditions. Significantly, the chemically modified dsRNA-binding PNA (dbPNA) shows selective binding to the dsRNA region in panhandle structure over a single-stranded RNA (ssRNA) and a dsDNA containing the same sequence. The panhandle structure is not accessible to traditional antisense DNA or RNA with a similar length. Conjugation of the dbPNA with an aminosugar neamine enhances the cellular uptake. We observed that 2-5 μM dbPNA-neamine conjugate results in a significant reduction of viral replication. In addition, the 10-mer dbPNA inhibits innate immune receptor RIG-I binding to panhandle structure and thus RIG-I ATPase activity. These findings would provide the foundation for developing novel dbPNAs for the detection of influenza viral RNAs and therapeutics with optimal antiviral and immunomodulatory activities.
ISSN: 1043-1802
DOI: 10.1021/acs.bioconjchem.9b00039
Rights: © 2019 American Chemical Society. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SPMS Journal Articles

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