20 years of DNA-encoded chemical libraries

Abstract

The identification of specific binding molecules is a central problem in chemistry, biology and medicine. Therefore, technologies, which facilitate ligand discovery, may substantially contribute to a better understanding of biological processes and to drug discovery. DNA-encoded chemical libraries represent a new inexpensive tool for the fast and efficient identification of ligands to target proteins of choice. Such libraries consist of collections of organic molecules, covalently linked to a unique DNA tag serving as an amplifiable identification bar code. DNA-encoding enables the in vitro selection of ligands by affinity capture at sub-picomolar concentrations on virtually any target protein of interest, in analogy to established selection methodologies like antibody phage display. Multiple strategies have been investigated by several academic and industrial laboratories for the construction of DNA-encoded chemical libraries comprising up to millions of DNA-encoded compounds. The implementation of next generation high-throughput sequencing enabled the rapid identification of binding molecules from DNA-encoded libraries of unprecedented size. This article reviews the development of DNA-encoded library technology and its evolution into a novel drug discovery tool, commenting on challenges, perspectives and opportunities for the different experimental approaches.

Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library

“…The affinity-based screening strategy is an ideal way to identify allosteric ligands for a receptor, and DEL screening is an innovative strategy to perform affinitybased selections against targets that are isolated or expressed on whole cells (12). Although this technique enables an unprecedented increase in the size of libraries that can be screened compared with conventional activity-based screening formats, its use has mostly been limited to soluble protein targets (12,13). Due to the inherent difficulty in isolating functional membrane proteins, this technique has been only rarely used to obtain ligands for GPCRs.…”

“…Another approach, which has not yet been widely applied, is screening of DNA-encoded small-molecule libraries (DELs). In this approach, remarkably large combinatorial libraries consisting of up to billions of small-molecule compounds are displayed on DNA fragments that serve as barcodes for their subsequent identification (12,13). In the past few years, application of the DEL screening technology for soluble proteins has produced inhibitors against cancer and immune disorders and against therapeutic targets.…”

Nucleic Acid-programmed Assemblies: Translating Instruction into Function in Chemical Biology

“…[21][22][23] The discovery of small molecules that perturb a given biological pathway by binding to a specific target lies at the core of chemical biology and drug discovery. While highthroughput screening (HTS) approaches have proven effective, there remains a need to accelerate the discovery of bioactive compounds and reduce the overall costs, particularly as chemical biology probes.…”

A Handbook for DNA‐Encoded Chemistry

“…Thanks to the striking sensitivity and specificity of small-molecule DNA-encoding/decoding, today DNA-Encoded Chemical Library (DECL) technology holds a concrete promise to elegantly tackle this formidable task. The appeal of DECL technology mainly relies on the unrivalled opportunity to rapidly synthesize and probe by means of simple affinitycapture selection procedures chemical libraries of unprecedented size in a single test tube [1][2][3][4][5][6].…”