A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure
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 cellu...
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Science::Chemistry dbPNA Influenza 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 A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure |
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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. |
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School of Physical and Mathematical Sciences |
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School of Physical and Mathematical Sciences 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 |
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Article |
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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 |
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Kesy, Julita |
title |
A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure |
title_short |
A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure |
title_full |
A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure |
title_fullStr |
A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure |
title_full_unstemmed |
A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure |
title_sort |
short chemically modified dsrna-binding pna (dbpna) inhibits influenza viral replication by targeting viral rna panhandle structure |
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2021 |
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https://hdl.handle.net/10356/150015 |
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sg-ntu-dr.10356-1500152021-05-31T02:41:06Z A short chemically modified dsRNA-Binding PNA (dbPNA) inhibits influenza viral replication by targeting viral RNA panhandle structure 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 School of Physical and Mathematical Sciences Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences NTU Institute of Structural Biology Science::Chemistry dbPNA Influenza 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. Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University National Medical Research Council (NMRC) This work was supported by National Science Centre Grant UMO-2015/19/B/NZ1/02803 to E.K. and Grant UMO-2016/21/N/NZ1/00565 to J.K., the Polish Ministry of Science and Higher Education under the KNOW program, Singapore Ministry of Education (MOE) Tier 1 Grants RGT3/13 and RG42/15 to G.C., MOE Tier 2 Grants MOE2013-T2-2-024 and MOE2015-T2-1-028 to G.C., NTU start-up grant and MOH NMRC Grant OFIRG17nov084 to D.L., Temasek Life Sciences Laboratory, Singapore (to M.P.), and Fondation pour la Recherche Med́icale and Agence Nationale de Recherche Programme Labex (ARCANE, ANR-11-LABX-003 to J.-L.D.). 2021-05-31T02:41:06Z 2021-05-31T02:41:06Z 2019 Journal Article 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. https://dx.doi.org/10.1021/acs.bioconjchem.9b00039 1043-1802 0000-0002-9887-128X 0000-0001-7058-1304 0000-0002-8772-9755 https://hdl.handle.net/10356/150015 10.1021/acs.bioconjchem.9b00039 30721034 2-s2.0-85063165182 3 30 931 943 en RGT3/13 RG42/15 MOE2013-T2-2-024 MOE2015-T2-1-028 OFIRG17nov084 Bioconjugate Chemistry © 2019 American Chemical Society. All rights reserved. |