Chemical Ligation of Oligonucleotide Tags to Support Encoded Chemical Library Synthesis

Chemical ligation can be used to install encoding tags during the synthesis of DNA-encoded chemical libraries and can present a number of advantages. Here we describe methods to generate polymerase-readable oligonucleotide junctions and for the polymerase-mediated amplification of oligonucleotides ligated with these chemistries, including triazole junctions generated from 2'-ribo-3'-propargyl and 5'-azido oligonucleotides and from 2'-deoxy-3'-propargyl and 5'-azido oligonucleotides. We also present methods for the synthesis of phosphorothioate junctions from 3'-thiophospho and 5'-iodo oligonucleotides and for the synthesis of phosphodiester junctions from both 3'-hydroxy and 5'-phospho- and 3'-phospho and 5'-hydroxy oligonucleotides using 1-cyanoimidazole.