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3.2.1.3 Chemical Ligation/Encoding

DOI: 10.1055/sos-SD-241-00198

Keefe, A. D.; Litovchick, A.Science of Synthesis: DNA Encoded Librariesearly view.

General Introduction

In order to generate a library of DNA-encoded chemical compounds it is necessary to covalently attach multiple encoding tracts of DNA to each compound. The most widely practiced methodology to achieve this utilizes synthetic oligodeoxynucleotide “tags” and small chemical compound “building blocks”, each bearing at least one functional group, and associates individual unique tag sequences with individual unique building blocks. Building blocks are successively installed over multiple cycles of chemistry conducted in a combinatorial fashion by splitting nascent library material into multiple compartments, conducting building block and tag installation in each compartment, followed by pooling. This version of DNA-encoded library (DEL) synthesis is by far the most widely practiced and is more specifically referred to as DNA-recorded chemical synthesis. The cloning and sequencing of library material provides individual sequence reads, from which concatenated oligonucleotide tag sequences can then be used to infer the identities of the building block combinations with which they are associated. Combining this approach with affinity-mediated selection allows for the identification of individual library members that can bind to targets of interest, usually proteins, and in doing so may modulate their biological function.

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References


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