Reversible Covalent Headpiece Enables Interconversion between Double‐ and Single‐Stranded DNA‐Encoded Chemical Libraries

Abstract

The use of a proper encoding methodology is one of the most important aspects when practicing DEL technology. A "headpiece"-based double-stranded DEL encoding method is currently the most widely used for productive DEL. However, the robustness of double-stranded DEL construction conflicts with the versatility presented by singlestranded DEL applications. We here report a novel encoding method, which is based on a "reversible covalent headpiece (RCHP)". The RCHP allows reversible interconversion between double-and single-stranded DNA formats, providing an avenue to robust synthesis and allowing for the applications in distinct setups. We have validated the versatility of this encoding method with encoded self-assembled chemical library and DNA-encoded dynamic library technology. Notably, based on the RCHP-settled library construction, a unique "ternary covalent complex" mediating ligand isolation methodology against non-immobilized targets was developed.

Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options

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DNA-Compatible ortho-Phthalaldehyde (OPA)-Mediated 2-Substituted Isoindole Core Formation and Applications

“…DNA-encoded chemical library (DEL) has been proved to be a powerful tool in hit discovery and widely accepted in both the pharmaceutical industry and academia during recent years. , In a DEL, each synthetic chemotype (chemical compound) is covalently tethered with an identical encoding genotype (DNA tag), and the spatial encoding in traditional high throughput screening is replaced with DNA encoding, therefore allowing the biologically active ligand discovery process at a relatively low cost. − The high level of productivity of DEL in hit discovery has been confirmed by preclinical and clinical drug candidates ranging from kinase inhibitors to epigenetic modulators. − The success of DELs heavily relies on the collection of compounds with drug-like properties. ,− Therefore, the development of DNA-compatible synthetic methods to expand the chemical composition of DEL is highly desired. − Critically, several methodologies have been developed recently to generate drug-like moieties with the encoded DNA tag. − While medicinal chemistry research has continuously witnessed drug-like moieties demonstrating fascinating pharmacological activities, there are still limitations in the expansion of DNA-compatible reactions in pursuit of drug-like moieties …”

Supernatural: Artificial Nucleobases and Backbones to Program Hybridization-Based Assemblies and Circuits

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