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

The use of viral protein inhibitors has shown to be insufficiently effective in the case of highly variable SARS-CoV-2. In this work, we examined the possibility of designing agents that bind to a highly conserved region of coronavirus (+)RNA. We demonstrated that while the design of antisense RNAs is based on the complementary interaction of nitrogenous bases, it is possible to use semirigid docking methods in the case of unnatural peptide nucleic acids. The transition from N-(2-aminoethyl)glycine chain to a more conformationally rigid piperidine-containing backbone allowed us to significantly increase the affinity of structures to the target RNA.