Mapping functionally relevant tractable lysines of challenging protein targets by covalent fragment screening

Csorba, Noémi (author), Ábrányi-Balogh, Péter (author), Orgován, Zoltán (author), Szalai, Tibor Viktor (author), Ferenczy, György G. (author), Kollár, Levente (author), Péczka, Nikolett (author), Imre, Tímea (author), Simon, József (author), Hrast Rambaher, Martina (author), Gobec, Stanislav (author)

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.

• Language: English
• Keywords: allosteric sites, covalent fragment, electrophilic warhead, lysine labelling, protein–protein interaction
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 11 str.
• Numbering: Vol. 27, iss. 11, art. e70421
• PID: 20.500.12556/RUL-185272
• UDC: 615.4:54
• ISSN on article: 1439-7633
• DOI: 10.1002/cbic.70421
• COBISS.SI-ID: 282801923
• Publication date in RUL: 30.07.2026

Record is a part of a journal

• Title: ChemBioChem
• Shortened title: ChemBioChem
• Publisher: Wiley-VCH-Verl..
• ISSN: 1439-7633
• COBISS.SI-ID: 519041305

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: alosterična mesta, kovalentni fragment, elektrofilna bojna glava, označevanje lizina, interakcija protein-protein, farmacevtska kemija