Chemoproteomics is an interdisciplinary field combining chemistry and proteomics to investigate proteins. It aims to understand how small molecules interact with proteins within biological systems. It is increasingly recognized for its role in biological research and drug development.
The Tools of Chemoproteomics
Chemoproteomics often uses specialized small molecules called chemical probes. These probes are designed to selectively bind to and identify proteins within complex biological mixtures. Chemical probes are categorized as affinity-based and activity-based. Affinity-based probes capture proteins based on noncovalent binding strength. Activity-based probes target proteins based on enzymatic activity, often forming a covalent bond with the active site.
Probes tag proteins, making them detectable for analysis. Activity-based probes typically include a reactive group, a reporter tag (like biotin or rhodamine), and a linker. Mass spectrometry is the primary analytical technique for identifying and quantifying tagged proteins. Improvements in mass spectrometry have enhanced chemoproteomics, allowing for more comprehensive identification and quantification of proteins in biological samples.
Uncovering Protein Function
Chemoproteomics provides insights into protein roles in cells and disease processes. It identifies the specific proteins that drugs or small molecules bind to, their “targets,” even if previously unknown. This is useful for understanding a drug’s “mechanism of action,” describing how it exerts effects at a molecular level. For example, chemoproteomics revealed that curcusone D targets Brat1, a protein that helps cancer cells grow by repairing DNA.
It also detects “off-target” effects, where a molecule binds to unintended proteins, potentially causing side effects. By mapping protein-small molecule interactions across the proteome, chemoproteomics helps anticipate and understand these effects. This understanding helps decipher disease pathways and cellular processes, providing a more complete picture of biological systems. For instance, chemoproteomics identified that panobinostat, a drug for multiple myeloma, binds to phenylalanine hydroxylase, causing hypothyroidism as an off-target effect.
Accelerating Drug Discovery
Chemoproteomics impacts drug discovery by identifying novel targets for various diseases. It explores the “undruggable space,” including proteins previously inaccessible to small molecule drugs due to a lack of defined binding pockets. This approach identifies new chemical scaffolds that interact with challenging targets, broadening therapeutic options. For example, chemoproteomics identified novel inhibitors for Hsp90, a protein linked to cancer.
It also optimizes drug candidates by providing information on their selectivity and potency. By mapping cellular proteins that interact with a drug candidate, chemoproteomics guides medicinal chemistry to improve efficacy and minimize unintended interactions. This iterative process, often involving competitive activity-based protein profiling (ABPP), refines compounds to achieve a desired target profile.
Chemoproteomics also helps understand drug resistance mechanisms, enabling new strategies to overcome them. For instance, in cancer treatment, understanding how cancer cells develop resistance (e.g., through altered protein expression or mutated protein-protein interfaces) is important. Insights from chemoproteomic studies can inform the design of combination therapies or new drug molecules that circumvent these mechanisms.
It also contributes to drug repurposing, finding new uses for existing drugs and saving time and resources. By identifying additional protein targets for approved drugs, chemoproteomics facilitates their application to other diseases, leveraging established safety profiles. This enables rapid translation of discoveries into new medicines, benefiting human health.