The tremendous potential of RNA-targeting therapeutics in the treatment of diverse disorders and diseases is widely recognized. Among these therapeutics, antisense oligonucleotides (ASOs) hold great promise due to their exceptional specificity and ability to dynamically adjust and accommodate changes in target sequences. Our ultimate goal is to develop antisense probes that can selectively bind to the target RNA and trigger a subsequent bioorthogonal ligation process, resulting in the interlocking of the target strand. The hybridization of these antisense probes with the target RNA induces steric proximity of the bioorthogonal tags, thereby expediting the subsequent bioorthogonal reaction. This innovative approach is not only anticipated to provide a versatile platform for various therapeutic strategies, including sequence-specific drug delivery, but also to offer valuable insights into intricate cellular processes.Peptide nucleic acids (PNAs) have emerged as a promising approach among antisense oligonucleotides, as they replicate the structure and function of nucleic acids while featuring a peptide backbone. Their attached nucleobases enable them to form hybridization complexes with complementary RNA strands, exhibiting high affinity and specificity for DNA and RNA targets, thus finding applications in gene targeting, antisense therapy, and molecular diagnostics.However, PNAs suffer from inherent low water solubility, which limits their use in biological systems and raises concerns about potential cytotoxicity.To address this issue, the concept of gamma-miniPEG-PNA has been introduced, where diethylene glycol groups are incorporated throughout the PNA back- bone.In this thesis, various PNAs and gamma-mini-PEG-PNAs were synthesized using solid-phase peptide synthesis, and their hybridization properties were compared to RNA using surface plasmon resonance (SPR) spectroscopy. To produce the an- tisense probes discussed above, initial functionalizations were being tested on PNAs.
