Mapping Functionally Relevant Tractable Lysines of Challenging Protein Targets by Covalent Fragment Screening

Csorba, Noémi and Ábrányi-Balogh, Péter and Orgován, Zoltán and Szalai, Tibor Viktor and Ferenczy, György G. and Kollár, Levente and Péczka, Nikolett and Imre, Timea and Simon, József and Szabó, Pál and Schlosser, Gitta and Hrast, Martina and Gobec, Stanislav and Ivanova, Varbina and Galdeano, Carles and Kopranovic, Aleksandra and Neumann, Marc and Meyer‐Almes, Franz‐Josef and Keserű, György Miklós (2026) Mapping Functionally Relevant Tractable Lysines of Challenging Protein Targets by Covalent Fragment Screening. CHEMBIOCHEM, 27 (11). No. e70421. ISSN 1439-4227 (print); 1439-7633 (online)

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Abstract

Covalent fragment screening has become an established strategy for identifying targetable amino acid residues or viable chemical starting points against challenging protein targets. In recent years, lysine has received growing interest as a nucleophilic residue suitable for covalent labelling. Herein, we present a lysine‐targeting covalent fragment library covering a wide range of warheads. The reactivity and stability of the library members have been systematically characterised, and the library has been subsequently screened against a set of therapeutically relevant and challenging protein targets. We have discovered suitable warheads against the targets and characterised binding sites via enzymatic digestion and modelling. These findings highlight the potential of lysine‐targeting covalent chemistry to expand binding site discovery and to support warhead optimisation for diverse protein targets in both medicinal chemistry and chemical biology applications.

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