Reduction of the environmental impact associated with the synthesis of γ-modified PNA

Peptide nucleic acids (PNAs) are synthetic analogs of nucleic acids in which the sugar-phosphate backbone has been replaced by a peptide-like chain, typically composed of N-(2-aminoethyl)-glycine units (Fig. 1a). This unique structure gives PNAs high chemical stability, resistance to enzymatic degradation, and stronger binding affinity to complementary DNA or RNA sequences due to the neutral backbone.1 These properties make PNAs valuable tools in molecular biology and biotechnology, particularly for gene targeting, antisense therapies, diagnostics, as molecular probes and for the targeting of DNA non-canonical secondary structures.2 Furthermore, the possibility of modifying the classic PNA peptide backbone allows tuning the PNA conformations and hybridization capability. The γ-substituted chiral PNA (Fig. 1b) has shown several advantages such as minimal self-aggregation, good solubility, and stronger PNA–DNA/RNA duplex formation thanks to backbone preorganization.3 PNAs are synthesized using the Solid-phase synthesis (SPS) approaches, which were initially developed for the synthesis of peptides. SPS has a significant environmental impact due to the large amount of waste it generates raising sustainability concerns in both research and industrial settings.4 Furthermore, the lack of commercial availability of γ-modified PNA monomers (Fig. 1c) not only leads to increased waste but also adds complexity and time to the overall synthetic process, making large-scale or routine production less sustainable and more resource-intensive. In this work, we aim to develop alternative synthetic routes for the synthesis of modified PNA monomers, with the goal of reducing the environmental impact associated with their production. By exploring more sustainable strategies, we hope to minimize waste generation and improve the overall sustainability of PNA synthesis.