Petri, László and Gabizon, Ronen and Péczka, Nikolett and Ábrányi-Balogh, Péter and Simon, József and Imre, Timea and Ferenczy, György and London, Nir and Keserű, György Miklós (2026) α-Halothioamide warheads with enhanced cysteine reactivity and specificity for covalent protein labelling. NATURE COMMUNICATIONS, 17 (1). No. 6824. ISSN 2041-1723
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Abstract
Covalent labelling is a promising modality relying on electrophilic warheads that form covalent bonds with their targets. Here we present the oxygen-to-sulfur exchange strategy, that transforms traditional carboxamides to thioamides, yielding electrophilic warheads, including chlorothioacetamides and fluorothioacetamides, with enhanced cysteine reactivity, while retaining aqueous stability and selectivity. We demonstrate their utility in targeted covalent inhibitor development targeting Janus kinase 3 and Bruton’s tyrosin kinase, when installed on relevant scaffolds and also in the development of antibody-drug conjugates. Next, alkyne-tagged α-halothioamide probes are evaluated by quantitative chemoproteomics. These studies reveal that the chlorothioacetamide probe preferentially labelled a distinct subset of the proteome, which results in Cys-targeted covalent phosphodiesterase 6δ labelling with functional impact. We discuss that the oxygen-to-sulfur exchange strategy offers alternative cysteine-specific thioamide-derived warheads and enables precise and even late-stage modulation of covalent reactivity, highlighting their promise for covalent probe design and applications in medicinal chemistry and chemical biology.
| Item Type: | Article |
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| Additional Information: | This work was supported by the National Research, Development and Innovation Office of Hungary (2020-1.1.2-PIACI-KFI-2020-00039, SNN 151010 and STARTING 152137) and PharmaLab (RRF-2.3.1-21-2022-00015) projects. We thank A. Csámpai for his valuable inspiration and the scientific community of ELTE Thematic Excellence Programme (Szint + ) supported by the Hungarian Ministry for Innovation and Technology. We acknowledge the Digital Government Development and Project Management Ltd. for awarding us access to the Komondor HPC facility based in Hungary. We thank the work of Á. Horváth and A. Egyed in the synthesis of chemical probes, A. D. Marton. for in vitro metabolism investigations and S. Spisák for cell viability measurements on Ramos cells. L. P. was supported by the UNKP-23-4 New National Excellence Programme of the Hungarian Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund, and P. Á.-B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. N. L. is supported by the Abisch-Frenkel foundation, European Research Council (ERC_CoG 101125683), the Honey and Dr. Barry Sherman Lab, Dr. Barry Sherman Institute for Medicinal Chemistry, Abisch-Frenkel RNA Therapeutics Center, Moross Integrated Cancer Center, Goldhirsh-Yellin Foundation, and Celia Zwillenberg-Fridman. Open access funding provided by HUN-REN Research Centre for Natural Sciences. |
| Subjects: | Q Science / természettudomány > Q1 Science (General) / természettudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 24 Sep 2026 09:39 |
| Last Modified: | 24 Sep 2026 09:39 |
| URI: | https://real.mtak.hu/id/eprint/247483 |
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