Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 22; p. 7728
• Main Authors: Huang, Fangjiao, Han, Xiaoli, Xiao, Xiaohui, Zhou, Jinming
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.11.2022; MDPI
• Subjects: Amino acids; Amino Acids - chemistry; Binding sites; Cancer; Catalysis; Cellular signal transduction; Chemical bonds; Chemical composition; Clopidogrel; Covalence; covalent inhibitor; covalent warheads; Cyclin-dependent kinases; Cysteine; Cysteine - chemistry; Drug Development; Drug resistance; Equilibrium; Gene expression; Kinases; Ligands; Mutation; Oxidation-Reduction; Proteins; Receptor mechanisms; Residues; Review; Signal transduction; Sitagliptin; Sulfhydryl Compounds - chemistry; Thiols; Warheads; covalent warheads; covalent inhibitor; cysteine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27227728

Cysteine is one of the least abundant amino acids in proteins of many organisms, which plays a crucial role in catalysis, signal transduction, and redox regulation of gene expression. The thiol group of cysteine possesses the ability to perform nucleophilic and redox-active functions that are not feasible for other natural amino acids. Cysteine is the most common covalent amino acid residue and has been shown to react with a variety of warheads, especially Michael receptors. These unique properties have led to widespread interest in this nucleophile, leading to the development of a variety of cysteine-targeting warheads with different chemical compositions. Herein, we summarized the various covalent warheads targeting cysteine residue and their application in drug development.