Irene Sánchez-Sordo, Manuel Nappi

Synthesis 

DOI: 10.1055/a-2881-8736

Abstract

DNA-encoded library (DEL) technology serves as a cornerstone of modern drug discovery, providing a cost-effective platform for the rapid interrogation of therapeutic candidates. However, the prerequisite for DNA-compatible synthetic reactions under aqueous conditions has historically constrained DEL chemical diversity to planar, C(sp²)-rich architectures, resulting from a reliance on traditional two-electron polar transformations. This short review evaluates recent advances in radical-mediated transformations as a powerful means to increase the chemical space of DELs. By facilitating access to three-dimensional sp³-rich scaffolds, these radical methodologies have the potential to significantly broaden the structural diversity of modern DELs.

Lei Feng,Yang Liu,Yiwei Zhang,Zhongjiao Fan,Xinyuan Wu,Xiancheng Yang,Leyi Liu,Zhibei Qu,Ying Shen,Xiaojie Lu,Lu Zhou

Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.6c00456

Abstract

Protein oligomerization is functionally essential for many enzymes, yet small-molecule strategies that directly target dimer interfaces remain challenging. Cysteine residues at protein dimer interfaces offer chemically addressable sites for modulating oligomeric assembly. Here, we used covalent DNA-encoded chemical library (CoDEL) screening to identify site-selective covalent hits targeting the PHGDH dimer interface. Covalent hits emerging from CoDEL screening were optimized to yield a selective covalent inhibitor engaging the interfacial Cys281. A representative compound, D5-2, potently disrupts PHGDH dimerization and inhibits its enzymatic activity, restores sensitivity to EGFR tyrosine kinase inhibitors in resistant lung adenocarcinoma cells in vitro, and exhibits antitumor efficacy in mouse xenograft models. Together, these findings establish dimer-interface cysteine targeting as a mechanism-based and therapeutically relevant strategy for modulating PHGDH function, and highlight the potential of CoDEL for discovering covalent inhibitors of protein-protein interfaces.

Simon H. Rüdisser, Gabriela Stadler, Alvar D. Gossert

Angewandte Chemie International Edition

DOI: 10.1002/anie.6036832

Abstract

Small‐molecule drug discovery typically begins with the screening of compound libraries to identify initial hits, which are subsequently optimized into lead compounds and, ultimately, drug candidates. Diverse screening methodologies are employed, including DNA‐encoded library technology, high‐throughput screening, and fragment‐based drug discovery (FBDD). Among these, FBDD is particularly powerful when integrated with structure‐guided drug design and biophysical affinity measurements. However, accurately quantifying the weak binding affinities of fragments remains a significant challenge. To address this, we introduce chemical shift anisotropy (CSAKD), a novel method for determining absolute fragment affinities using NMR relaxation. The CSAKD approach eliminates the need for titration experiments and isotopic labeling. Furthermore, we complement this method with a machine learning model for the rapid and accurate prediction of chemical shielding tensors. In summary, CSAKD allows fast and efficient affinity determination which seamlessly integrates into FBDD by NMR.

Seok Ju Hong, Dong Hyeon Kim, Yujin Lim, Yongseok Kwon, Sangkyu Lee, Han Yong Bae

Advanced Functional Materials

DOI: 10.1002/adfm.76220

Abstract

Sulfur fluoride exchange (SuFEx) has emerged as a powerful click platform for the construction of functional molecules and advanced materials. However, the lack of water‐compatible, structurally versatile SuFEx‐active linchpins has limited their broader implementation in modular molecular engineering and in DNA‐based bioconjugates. Here, we introduce a diazonium linchpin platform that enables rapid molecular diversification and direct DNA functionalization under mild and scalable conditions. The linchpins are prepared through a chromatography‐free, decagram‐scale synthesis to afford aryldiazonium tetrafluoroborates that exhibit exceptional stability toward oxygen and aqueous environments. These multifunctional building blocks undergo rapid Pd(II)‐catalyzed cross‐coupling in aqueous media, delivering structurally diverse aryl sulfonyl fluorides in 10 min with good functional‐group tolerance. This platform further extends to halo‐ and azido‐functionalized SuFEx hubs, providing streamlined access to triazenes, sulfonates, sulfonamides, and sulfonyl azides as versatile connectors for functional molecular assembly. More importantly, the intrinsic water compatibility of this system enables highly efficient, catalyst‐free on‐DNA SuFEx ligation with amino‐ and phenol‐modified double‐stranded DNA headpieces, directly integrating small‐molecule diversification with biomolecular conjugation. By unifying rapid, scalable aqueous diversification with bioorthogonal functionalization, this work tentatively establishes a versatile, small‐molecule materials‐oriented strategy for constructing SuFEx‐active molecular libraries and DNA‐conjugated architectures, including DNA‐encoded libraries.

Shaoren Yuan , Baljit Kaur , Natalie Fuchs , Sungwoo Cho , Ashraf Abdo , Moustafa Gabr

RSC Chemical Biology

DOI: 10.1039/d6cb00117c

Abstract

Peptides have evolved from naturally occurring ligands and classical hormones into a versatile and engineerable class of functional molecules. This review provides a comprehensive overview of the technological advances that collectively enable programmable peptide engineering across the entire discovery-to-development pipeline. We first discuss innovations in automated flow synthesis, chemoselective ligation, noncanonical residue incorporation, backbone editing, conformational constraint, and late-stage functionalization that have transformed peptide chemistry from linear sequence assembly into a modular engineering platform. We then examine modern discovery approaches including phage display, mRNA display with the RaPID system, and DNA-encoded chemical libraries, alongwith computational and AI-enabled design strategies that accelerate hit identification and multi parameter optimization. Biophysical characterization techniques, cellular target engagement assays, and emerging delivery strategies are also reviewed as critical tools for bridging biochemical potency with intracellular activity. Finally, we discuss the translational barriers facing peptide therapeutics and the engineering strategies that have enabled successful clinical applications. Together, these advances establish a new era which peptides are no longer viewed as inherently labile biomolecules but as chemically programmable scaffolds whose structures and functions can be precisely engineered.

Zhaobing Ding, Feifei Li, Jun Lu, Bing Qi

Organic Letters

DOI: 10.1021/acs.orglett.6c01786

Abstract

Here, we report a mild and DNA-compatible cyclization strategy for the construction of [1,2,4]triazolo[1,5-a]pyridine scaffolds that is well suited for DNA-encoded library (DEL) construction. This reaction proceeds via cyclocondensation of aldehydes with 1,2-diaminopyridinium salt substrates under mild and simple conditions. This method enables the rapid and efficient construction of a series of DNA-encoded libraries containing compounds with a potentially biologically active [1,2,4]triazolo[1,5-a]pyridine scaffold.