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A Short Chemically Modified dsRNA-Binding PNA (dbPNA) Inhibits Influenza Viral Replication by Targeting Viral RNA
Julita Kesy1, Kiran M Patil2, Subaschandrabose Rajesh Kumar3
1Institute of Bioorganic Chemistry, Polish Academy of Sciences , Noskowskiego 12/14 , 61-704 Poznan , Poland.
Bioconjugate Chemistry
|February 6, 2019
Summary
Chemically modified peptide nucleic acids (PNAs) bind specifically to influenza A virus RNA, inhibiting viral replication and immune response. This discovery paves the way for novel antiviral therapies and diagnostics.
Area of Science:
- Biochemistry
- Molecular Biology
- Antiviral Therapeutics
Background:
- RNA molecules are crucial in biological processes and serve as disease biomarkers and therapeutic targets.
- Targeting specific RNA structures with chemical compounds offers significant biomedical potential.
- Influenza A virus RNA contains a conserved panhandle structure essential for its replication.
Purpose of the Study:
- To design and evaluate a chemically modified double-stranded RNA (dsRNA)-binding peptide nucleic acid (PNA) for targeting the influenza A virus panhandle structure.
- To assess the binding specificity, cellular uptake, and antiviral activity of the modified PNA.
Main Methods:
- Synthesis of a 10-mer chemically modified dsRNA-binding PNA (dbPNA) incorporating specific modified residues (L and Q).
- Assessing PNA binding to the influenza A virus panhandle structure using biophysical methods.
- Evaluating the antiviral activity of dbPNA-neamine conjugates in cell culture against influenza A.
- Investigating the inhibition of RIG-I binding and ATPase activity by dbPNA.
Main Results:
- The modified dbPNA demonstrated sequence-specific binding to the dsRNA panhandle structure, forming a PNA·RNA2 triplex.
- dbPNA selectively bound the dsRNA panhandle over single-stranded RNA and double-stranded DNA.
- Conjugation with neamine enhanced cellular uptake, and 2-5 μM dbPNA-neamine conjugate significantly reduced viral replication.
- dbPNA inhibited RIG-I receptor binding to the viral RNA, consequently reducing RIG-I ATPase activity.
Conclusions:
- Chemically modified dbPNAs can effectively target the conserved influenza A virus panhandle structure.
- dbPNA-neamine conjugates exhibit potent antiviral activity and immunomodulatory effects by inhibiting viral replication and innate immune pathways.
- These findings support the development of novel dbPNAs for influenza diagnostics and therapeutics.
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