Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis.

The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead-based synthesis.

Asymmetry of Dual-Display DNA-Encoded Chemical Libraries.

While dual-display DNA-encoded chemical libraries (DELs) are increasingly employed for ligand discovery, some of their fundamental properties have not yet been studied in-depth. Aided with fluorescence polarization experiments, we demonstrate that dual-display DELs are intrinsically asymmetrical entities, and we deduce practical guidelines to perform better-informed on-DNA hit validation from these libraries.

Universal encoding of next generation DNA-encoded chemical libraries.

DNA-encoded chemical libraries (DELs) are useful tools for the discovery of small molecule ligands to protein targets of pharmaceutical interest. Compared with single-pharmacophore DELs, dual-pharmacophore DELs simultaneously display two chemical moieties on both DNA strands, and allow for the construction of highly diverse and pure libraries, with a potential for targeting larger protein surfaces. Although methods for the encoding of simple, fragment-like dual-display libraries have been established, more complex libraries require a different encoding strategy.

Macrocyclic DNA-encoded chemical libraries: a historical perspective.

While macrocyclic peptides are extensively researched for therapeutically relevant protein targets, DNA-encoded chemical libraries (DELs) are developed at a quick pace to discover novel small molecule binders. The combination of both fields has been explored since 2004 and the number of macrocyclic peptide DELs is steadily increasing. Macrocycles with high affinity and potency were identified for diverse classes of proteins, revealing DEL's huge potential.

Modular assembly and encoding strategies for dual-display DNA-encoded chemical libraries.

DNA-encoded chemical libraries (DELs) are increasingly being used for the discovery of protein ligands and can be constructed displaying either one or two molecules at the extremities of the two complementary DNA strands. Here, we describe that DELs, featuring the simultaneous display of two molecules, can be encoded using various types of DNA structures, which go beyond the use of conventional double-stranded DNA fragments. Specifically, we compared dual-display methodologies in hairpin, circular or linear formats in terms of polymerase chain reaction (PCR) amplifiability and performance in affinity capture selections.

A DNA-Encoded Chemical Library Based on Peptide Macrocycles.

The synthesis and characterization of a novel DNA-encoded library of macrocyclic peptide derivatives are described; the macrocycles are based on three sets of proteinogenic and non-proteinogenic amino acid building blocks and featuring the use of copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction for ring closure. The library (termed YO-DEL) which contains 1 254 838 compounds, was encoded with DNA in single-stranded format and was screened against target proteins of interest using affinity capture procedures and photocrosslinking. YO-DEL selections yielded specific binders against serum albumins, carbonic anhydrases and NKp46, a marker of activated Natural Killer cells.