A Single‐Stranded DNA‐Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks

• Main Authors: Gabriele Bassi, Nicholas Favalli, Miriam Vuk, Marco Catalano, Adriano Martinelli, Anika Trenner, Antonio Porro, Su Yang, Chuin Lean Tham, Mustafa Moroglu, Wyatt W. Yue, Stuart J. Conway, Peter K. Vogt, Alessandro A. Sartori, Jörg Scheuermann, Dario Neri
• Format: Article
• Language: English
• Published: Wiley 2020-11-01
• Series: Advanced Science
• Subjects: Human alpha‐aminoadipic semialdehyde synthase (AASS); affinity maturation; cyclic‐AMP response element binding protein (CREBBP); DNA‐encoded chemical libraries (DEL); drug discovery; encoded self‐assembling chemical libraries (ESAC)
• Online Access: https://doi.org/10.1002/advs.202001970
• ISSN: 2198-3844

Abstract A versatile and Lipinski‐compliant DNA‐encoded library (DEL), comprising 366 600 glutamic acid derivatives coupled to oligonucleotides serving as amplifiable identification barcodes is designed, constructed, and characterized. The GB‐DEL library, constructed in single‐stranded DNA format, allows de novo identification of specific binders against several pharmaceutically relevant proteins. Moreover, hybridization of the single‐stranded DEL with a set of known protein ligands of low to medium affinity coupled to a complementary DNA strand results in self‐assembled selectable chemical structures, leading to the identification of affinity‐matured compounds.