Covalent fragment approaches targeting non-cysteine residues

• Published in: Trends in pharmacological sciences (Regular ed.) 2023-11, Vol.44 (11), p.802-816
• Main Authors: Csorba, Noémi, Ábrányi-Balogh, Péter, Keserű, György M.
• Format: Article
• Language: English
• Subjects: amino acid labeling; covalent fragment; covalent labeling; covalent warheads; fragment-based drug discovery; photocatalysis
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2023.08.014

The available collection of warheads has been extended to target a wider range of amino acid residues beyond cysteine enabling the identification of a larger pool of proteins.Covalent labeling can be achieved by noncatalytic chemical reactions; however, catalytic labeling achieved by heterogenous catalysts, photo- or electrocatalysis is an emerging field increasing the toolkit of specific labeling reactions. Photo- and electrocatalysis provide additional options for conditional labeling.Covalent fragments allow target identification by chemoproteomic techniques and enable identifying new (allosteric) binding sites.Covalent fragments can be considered as viable chemical starting points of targeted covalent ligands for target validation, molecular glues, and proteolysis-targeting chimeras (PROTACs). Covalent fragment approaches combine advantages of covalent binders and fragment-based drug discovery (FBDD) for target identification and validation. Although early applications focused mostly on cysteine labeling, the chemistries of available warheads that target other orthosteric and allosteric protein nucleophiles has recently been extended. The range of different warheads and labeling chemistries provide unique opportunities for screening and optimizing warheads necessary for targeting non-cysteine residues. In this review, we discuss these recently developed amino-acid-specific and promiscuous warheads, as well as emerging labeling chemistries, which includes novel transition metal catalyzed, photoactive, electroactive, and noncatalytic methodologies. We also highlight recent applications of covalent fragments for the development of molecular glues and proteolysis-targeting chimeras (PROTACs), and their utility in chemical proteomics-based target identification and validation. Covalent fragment approaches combine advantages of covalent binders and fragment-based drug discovery (FBDD) for target identification and validation. Although early applications focused mostly on cysteine labeling, the chemistries of available warheads that target other orthosteric and allosteric protein nucleophiles has recently been extended. The range of different warheads and labeling chemistries provide unique opportunities for screening and optimizing warheads necessary for targeting non-cysteine residues. In this review, we discuss these recently developed amino-acid-specific and promiscuous warheads, as well as emerging labeling chemistries, which includes novel transition me