Advancing Covalent Ligand and Drug Discovery beyond Cysteine DOI Creative Commons
Gibae Kim, R. Justin Grams, Ku‐Lung Hsu

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: May 22, 2025

Targeting intractable proteins remains a key challenge in drug discovery, as these often lack well-defined binding pockets or possess shallow surfaces not readily addressed by traditional design. Covalent chemistry has emerged powerful solution for accessing protein sites difficult to ligand regions. By leveraging activity-based profiling (ABPP) and LC-MS/MS technologies, academic groups industry have identified cysteine-reactive ligands that enable selective targeting of challenging modulate previously inaccessible biological pathways. Cysteines within are rare, however, developing covalent target additional residues hold great promise further expanding the ligandable proteome. This review highlights recent advancements amino acids beyond cysteine with an emphasis on tyrosine- lysine-directed their applications chemical biology therapeutic development. We outline process using proteomic methodology, highlighting successful examples discuss considerations future expansion acid proteins.

Language: Английский

Advancing Covalent Ligand and Drug Discovery beyond Cysteine DOI Creative Commons
Gibae Kim, R. Justin Grams, Ku‐Lung Hsu

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: May 22, 2025

Targeting intractable proteins remains a key challenge in drug discovery, as these often lack well-defined binding pockets or possess shallow surfaces not readily addressed by traditional design. Covalent chemistry has emerged powerful solution for accessing protein sites difficult to ligand regions. By leveraging activity-based profiling (ABPP) and LC-MS/MS technologies, academic groups industry have identified cysteine-reactive ligands that enable selective targeting of challenging modulate previously inaccessible biological pathways. Cysteines within are rare, however, developing covalent target additional residues hold great promise further expanding the ligandable proteome. This review highlights recent advancements amino acids beyond cysteine with an emphasis on tyrosine- lysine-directed their applications chemical biology therapeutic development. We outline process using proteomic methodology, highlighting successful examples discuss considerations future expansion acid proteins.

Language: Английский

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