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

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

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.

• Jezik: Angleški jezik
• Ključne besede: allosteric sites, covalent fragment, electrophilic warhead, lysine labelling, protein–protein interaction
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: 11 str.
• Številčenje: Vol. 27, iss. 11, art. e70421
• PID: 20.500.12556/RUL-185272
• UDK: 615.4:54
• ISSN pri članku: 1439-7633
• DOI: 10.1002/cbic.70421
• COBISS.SI-ID: 282801923
• Datum objave v RUL: 30.07.2026

Gradivo je del revije

• Naslov: ChemBioChem
• Skrajšan naslov: ChemBioChem
• Založnik: Wiley-VCH-Verl..
• ISSN: 1439-7633
• COBISS.SI-ID: 519041305

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: alosterična mesta, kovalentni fragment, elektrofilna bojna glava, označevanje lizina, interakcija protein-protein, farmacevtska kemija