Methods for tagging dna-encoded libraries

Abstract

The present invention relates to methods for producing encoded chemical entities. In particular, the oligonucleotides and methods can include encoded chemical entities having wild-type linkages formed through chemical ligation techniques. One strategy that can be utilized that simultaneously takes advantage of chemical ligation as a means to encode chemical history, while also retaining the ability of polymerases to directly recover tag sequence and association information, is to perform chemical ligation in a manner that generates wildtype phosphodiester linkages. Such methods generally utilize condensing agents such as cyanogen bromide or similar along with 5'-phosphate and 3'-hydroxyl oligonucleotides in a double-stranded or templated context. Similarly cyanogen bromide has also been shown to chemically ligate pairs of substrate oligonucleotides that are 5'-hydroxyl and 3'-phosphate. However, these methods suffer from poor efficiency making them ill-suited for use in an iterative process such as tagging DNA-encoded libraries.

Description

Background of the invention

[0001] DNA-encoded chemical library members are chemical entities generated by combinatorial chemical synthesis methods that are associated with combinations of encoding oligonucleotide tags. The combination of markers associated with individual library members can be determined and used to deduce the chemical synthesis history of the associated library member.

[0002] One method for generating such libraries is a method in which oligonucleotide tags are serially chemically ligated to head fragment oligonucleotides by successive split-mix steps, thereby revealing a chemically generated entity. In each resolution step, a chemical synthesis step is performed together with an oligonucleotide ligation step.

[0003] A chemically-mediated rather than an enzyme-mediated oligonucleotide ligation step allows greater flexibility with solution conditions and can reduce buffer exchange steps that may be necessary for thousands of small volumes of individual ...

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