Home  About us  Contact
 

Chemical Proteomics (chemical + proteomic)

Distribution by Scientific Domains
Chemistry75%

Selected Abstracts

Off-Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

CHEMBIOCHEM, Issue 7 2009
Enrico Missner
Abstract Unbiased: Chemical proteomics was used to profile compound interactions in an unbiased fashion. We present here the application of different compound-immobilization routes for decoding nonprotein kinase off-targets of the multitarget kinase inhibitor C1, which interacts with distinct compound moieties. Since the approval of the first selective tyrosine kinase inhibitor, imatinib, various drugs have been developed to target protein kinases. However, due to a high degree of structural conservation of the ATP binding site, off-target effects have been reported for several drugs. Here, we report on off-target decoding for a multitarget protein kinase inhibitor by chemical proteomics, by focusing on interactions with nonprotein kinases. We tested two different routes for the immobilization of the inhibitor on a carrier matrix, and thus identified off-targets that interact with distinct compound moieties. Besides several of the kinases known to bind to the compound, the pyridoxal kinase (PDXK), which has been described to interact with the CDK inhibitor (R)-roscovitine, was captured. The PDXK,inhibitor interaction was shown to occur at the substrate binding site rather than at the ATP binding site. In addition, carbonic anhydrase 2 (CA2) binding was demonstrated, and the determination of the IC50 revealed an enzyme inhibition in the submicromolar range. The data demonstrate that different compound immobilization routes for chemical proteomics approaches are a valuable method to improve the knowledge about the off-target profile of a compound. [source]

Click Chemistry-Led Advances in High Content Functional Proteomics

MOLECULAR INFORMATICS, Issue 11-12 2007

Abstract The availability of complete genome sequences for numerous eukaryotic and prokaryotic organisms has inspired the advent of new methods to functionally characterize proteins on a global scale. Chemical approaches, in particular, have emerged as a powerful way to investigate the proteome, providing small-molecule probes that report on protein activity and Post-Translational Modification (PTM) state directly in complex biological samples. Many of the key advances made in chemical proteomics can be attributed to the development of efficient bio-orthogonal reactions such as the copper (I)-catalyzed Huisgen's azide,alkyne cycloaddition, a reaction commonly known as "Click Chemistry" (CC). The generation of "clickable" proteomics probes has removed the requirement for bulky reporter tags, thereby allowing access to more biologically relevant systems such as live cells or animals. The versatility of CC has also allowed for greater experimental efficiency, as different reporter tags (i.e., a fluorophore for detection or biotin for enrichment) can be appended to a single probe. Such advances have enabled researchers to identify protein activities dysregulated in disease states, assess the selectivity of enzyme inhibitors in vivo, and inventory specific PTMs on a proteome-wide scale. [source]

Proteomics meets microbiology: technical advances in the global mapping of protein expression and function

CELLULAR MICROBIOLOGY, Issue 8 2005
Carolyn I. Phillips
Summary The availability of complete genome sequences for a large number of pathogenic organisms has opened the door for large-scale proteomic studies to dissect both protein expression/regulation and function. This review highlights key proteomic methods including two-dimensional gel electrophoresis, reference mapping, protein expression profiling and recent advances in gel-free separation techniques that have made a significant impact on the resolution of complex proteomes. In addition, we highlight recent developments in the field of chemical proteomics, a branch of proteomics aimed at functionally profiling a proteome. These techniques include the development of activity-based probes and activity-based protein profiling methods as well as the use of synthetic small molecule libraries to screen for pharmacological tools to perturb basic biological processes. This review will focus on the applications of these technologies to the field of microbiology. [source]

Off-Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

CHEMBIOCHEM, Issue 7 2009
Enrico Missner
Abstract Unbiased: Chemical proteomics was used to profile compound interactions in an unbiased fashion. We present here the application of different compound-immobilization routes for decoding nonprotein kinase off-targets of the multitarget kinase inhibitor C1, which interacts with distinct compound moieties. Since the approval of the first selective tyrosine kinase inhibitor, imatinib, various drugs have been developed to target protein kinases. However, due to a high degree of structural conservation of the ATP binding site, off-target effects have been reported for several drugs. Here, we report on off-target decoding for a multitarget protein kinase inhibitor by chemical proteomics, by focusing on interactions with nonprotein kinases. We tested two different routes for the immobilization of the inhibitor on a carrier matrix, and thus identified off-targets that interact with distinct compound moieties. Besides several of the kinases known to bind to the compound, the pyridoxal kinase (PDXK), which has been described to interact with the CDK inhibitor (R)-roscovitine, was captured. The PDXK,inhibitor interaction was shown to occur at the substrate binding site rather than at the ATP binding site. In addition, carbonic anhydrase 2 (CA2) binding was demonstrated, and the determination of the IC50 revealed an enzyme inhibition in the submicromolar range. The data demonstrate that different compound immobilization routes for chemical proteomics approaches are a valuable method to improve the knowledge about the off-target profile of a compound. [source]