A Catalytic Approach for the Synthesis of Peptide−Oligonucleotides Conjugates in Aqueous Solution or On‐Column

Peptide−oligonucleotide conjugates (POCs) are covalent architectures composed of a DNA or RNA molecules linked to a peptide. These constructs have found widespread applications ranging from hybrid nanomaterials to gene‐targeted therapies. Considering the important role of POCs, a new catalytic approach for their preparation is reported here, that could be applied either on solid support in anhydrous media, or post‐synthetically in aqueous buffer. Single amino acids, peptides and cell penetrating peptides (CPPs) were conjugated to various oligo(ribo)nucleotides with high conversions and good isolated yields. The applicability of the method was demonstrated on more than 35 examples including an analogue of a commercial therapeutic oligonucleotide. Other conjugation partners, such as deoxycholic acid and biotin were also successfully conjugated to oligonucleotides. To highlight the potential of this catalytic approach, these conditions have been applied to iterative processes, which is of high interest for the development of DNA‐Encoded Libraries. A new method for the preparation of peptide−oligonucleotide conjugates is presented herein. A catalytic DABCO/chlorotriazine system allowed the synthesis both on solid support in anhydrous media and in aqueous solution. More than 35 examples showcased the utility of the method with wide varieties of acid partners, peptides, and oligonucleotides, as well as an iterative process for DEL application.