From green innovations in oligopeptide to oligonucleotide sustainable synthesis: differences and synergies in TIDES chemistry

The growing market for therapeutic peptides and oligonucleotides (TIDES) draws attention towards their manufacture, aiming at efficient and sustainable productive processes in view of the predicted massive application of these molecules in several therapeutic areas in the near future. A comparative assessment of the principal innovations in the synthesis of these molecules is described herein, with a major focus on solid-phase synthesis (SPS), describing particularly the less-explored field of solid-phase oligonucleotide synthesis (SPOS). A head-to-head analysis of SPS techniques applied to peptides and oligonucleotides was performed, highlighting the strengths and weaknesses of these iterative synthetic approaches. The green innovations introduced in solid-phase peptide synthesis (SPPS), namely reduction or replacement with greener alternatives of solvents and reagents, and implementations in purification techniques, were reviewed and projected to potential targets and sustainable practices in modern SPOS, including their application in P(v) chemistry for the synthesis of stereopure oligonucleotides. By a comparative analysis, the key elements for the development of overall green procedures for oligonucleotide manufacturing were emphasized. In addition, due to the intrinsically more sustainable profile of liquid-phase synthetic techniques (LPS), recent advancements in the field reported for both TIDES were analyzed to prove the industrial interest in the manufacturing of these classes of molecules, underlining the importance of investment and modernization in the development of stronger and greener synthetic pathways.