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1 Introduction

DOI: 10.1055/sos-SD-241-00255

Scheuermann, J.; Li, Y.Science of Synthesis: DNA-Encoded Libraries, (202415.

The field of DNA-Encoded Chemical Libraries (DELs or DECLs)[‌1‌‌3‌] has gained rapid momentum over the last few years, as evidenced by the first DEL-derived small molecules having reached clinical trials and which thus might enter the pharmaceutical market.[‌4‌]

After the concept of encoding small molecules with a DNA barcode was first proposed by Sydney Brenner and Richard Lerner, and independently by Mark Gallop, in 1992,[‌5‌,‌6‌] it took quite a while until practical utility could be demonstrated for ligand discovery. Hampered by the difficult combination of peptide and oligonucleotide synthesis, new strategies needed to be elaborated in order to render the concept practically applicable. Indeed, this sleeping beauty lay dormant for a decade until new ideas were conceived that ignited the field.

Two major lines of study were investigated in the early 2000s. The first approach was established by David R. Liu from Harvard University by using ingenious DNA-templated chemistry for DEL construction,[‌7‌] while the second line could be termed DNA-recorded chemistry, and was based on combinatorial chemistry alternated with encoding. The latter was pioneered by academia (ETH Zürich)[‌8‌‌10‌] and industry (Praecis, now GSK),[‌11‌] who published the first recorded DELs, and has now become the industry standard. Today, DEL technology is practiced by many pharmaceutical companies for in-house drug discovery, by various specialized CROs, and by a few academic groups, including our own.

We feel very honored to present this volume of Science of Synthesis on DELs, with contributions from pioneers and major players from both industry and academia. The volume touches on all aspects of DEL technology, covering DEL chemistry, DEL encoding, DEL selection technologies against biological targets, and selection evaluation and follow-up.[‌12‌]

The volume opens with a foreword “DNA-Encoded Chemical Libraries: Past, Present, and Future” by Prof. Dario Neri, a pioneer of the field at ETH Zürich, with whom we have had the pleasure to work in the past.

The first section then details DNA-compatible reactions, with contributions from Chongqing University for amide-bond-forming reactions, Philochem for metal-promoted DEL-compatible CC bond forming reactions, WuXi AppTec for metal-free DEL-compatible CC bond forming reactions, ShanghaiTech University for on-DNA CX (X = N, O, P, S, Se) bond forming reactions, Shanghai Institute of Materia Medica for on-DNA CH transformations, University of Pennsylvania for on-DNA photoredox-catalyzed reactions, HitGen for on-DNA cyclization reactions, University of Würzburg for DNA-encoded isocyanide multicomponent reactions, Janssen for on-DNA functional-group transformations, University of Utah for reversible immobilization of DNA for chemical modification and for covalent attachment on a solid support, and Newcastle University (UK) for micelle-mediated synthesis.

The next section covers various DEL setups and encodings with contributions from Chongqing University on DNA-templated synthesis, Shenzhen Innovation Center for Small Molecule Drug Discovery on encoding using double-stranded DNA (“headpiece strategy”), Philochem for encoding using single-stranded DNA (“iterative splint-ligation”), X-Chem for chemical ligation/encoding, Philochem for encoded self-assembling chemical libraries, University of Geneva for peptide nucleic acid (PNA) encoded libraries, Technical University of Dresden/DyNAbind for DNA-encoded dynamic combinatorial chemical libraries, University of Basel for macrocyclic DELs, and ShanghaiTech University for natural-product-enriched DELs.

The following section presents various DEL selection procedures, with chapters from ETH Zürich for DEL selections by affinity-capture on solid support, University of Hong Kong for DEL selections using DNA-programmed affinity labelling (DPAL), and Purdue University for selections of DNA-encoded libraries on living cells and within living cells.

The volume concludes with chapters on informatic tools, processing, and evaluation of DEL selection data (WuXi AppTec), and on-DNA resynthesis and affinity selection mass spectrometry (ASMS) for hit validation (WuXi AppTec, Pfizer, XtalPi).

We hope this volume will provide a tutorial overview of all of aspects of DEL technology, showing how the field has evolved over the past 20 years, and that it will provide practical information for all scientists who are interested in using DEL technology.

We are most grateful to all the authors for their valuable contributions to realize this volume. We would further like to express our deep gratitude to the Science of Synthesis editorial team, in particular Dr. Alex Russell, Dr. Toby Reeve, and Ms. Michaela Frey, for their great efforts and their great support.