Rational Design Problematics of Peptide Nucleic Acids as SARS-CoV-2 Inhibitors.

Area of Science:

• Virology
• Molecular Biology
• Medicinal Chemistry

Background:

• Highly variable SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) necessitates alternative therapeutic strategies beyond protein inhibitors.
• Viral protein inhibitors demonstrate limited efficacy against rapidly mutating viruses like SARS-CoV-2.
• Targeting conserved regions of the viral genome presents a viable approach for developing broad-spectrum antiviral agents.

Purpose of the Study:

• To investigate the design of novel agents targeting highly conserved regions of coronavirus positive-sense single-stranded RNA ((+)RNA).
• To explore the potential of unnatural peptide nucleic acids (PNAs) as therapeutic agents against SARS-CoV-2.
• To enhance the binding affinity of PNAs to the target viral RNA through backbone modification.

Main Methods:

• Utilized semirigid docking methods for designing unnatural peptide nucleic acids.
• Investigated the interaction between modified PNAs and a conserved region of coronavirus (+)RNA.
• Synthesized and characterized PNAs with varying backbone structures, including N-(2-aminoethyl)glycine and piperidine-containing backbones.

Main Results:

• Demonstrated that semirigid docking is applicable for designing PNAs, unlike traditional antisense RNA design based on base complementarity.
• Identified that a transition to a more conformationally rigid piperidine-containing backbone significantly increased PNA affinity to the target RNA.
• Achieved a substantial enhancement in binding affinity through backbone structural modifications.

Conclusions:

• Unnatural peptide nucleic acids with modified backbones represent a promising strategy for targeting conserved viral RNA sequences.
• The developed PNA design approach offers a potential alternative to less effective protein inhibitors for highly variable viruses like SARS-CoV-2.
• Further development of conformationally rigid PNAs could lead to novel antiviral therapeutics with improved efficacy.