scholarly journals Parallel Evaluation of Nucleophilic and Electrophilic Chemical Probes for Sulfenic Acid: Reactivity, Selectivity and Biocompatibility

2021 ◽  
Author(s):  
Yunlong Shi ◽  
Kate S Carroll
Keyword(s):  
Hydrogen Peroxide ◽  
Small Molecule ◽  
Posttranslational Modification ◽  
Chemical Nature ◽  
Chemical Probes ◽  
Sulfenic Acid ◽  
Important Intermediate ◽  
Parallel Evaluation ◽  
Cysteine Thiols ◽  
Protein Models

S-sulfenylation of cysteine thiols (Cys-SOH) is a regulatory posttranslational modification in redox signaling and an important intermediate to other cysteine chemotypes. Owing to the dual chemical nature of the sulfur in sulfenic acid, both nucleophilic and electrophilic chemical probes have been developed to react with and detect Cys-SOH; however, the efficiency of existing probes has not been evaluated in a side-by-side comparison. Here, we employ small-molecule and protein models of Cys-SOH and compare the chemical probe reactivity. These data clearly show that 1,3-diketone-based nucleophilic probes react more efficiently with sulfenic acid as compared to strained alkene/alkyne electrophilic probes. Kinetic experiments that rigorously address the selectivity of the 1,3-diketone-based probes are also reported. Consideration of these data alongside relative cellular abundance, indicates that biological electrophiles, including cyclic sulfenamides, aldehydes, disulfides and hydrogen peroxide, are not meaningful targets of 1,3-diketone-based nucleophilic probes, which still remain the most viable tools for the bioorthogonal detection of Cys-SOH.

scholarly journals Proteome-Wide Survey Reveals Norbornene Is Complementary to Dimedone and Related Nucleophilic Probes for Cysteine Sulfenic Acid

2019 ◽  
Author(s):  
Lisa Alcock ◽  
Maike Langini ◽  
Kai Stühler ◽  
Marc Remke ◽  
Michael Perkins ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Chemical Reactivity ◽  
Live Cells ◽  
Chemical Probes ◽  
Cysteine Oxidation ◽  
Sulfenic Acid ◽  
Proteomics Analysis ◽  
New Members ◽  
Specific Chemical ◽  
Future Studies

<p>Detection of cysteine sulfenic acid in live cells is critical in advancing our understanding of cysteine redox chemistry and its biological function. Accordingly, there is a need to develop sulfenic acid-specific chemical probes with distinct reaction mechanisms to facilitate proteome-wide detection of this important posttranslational modification. Herein, we report the first whole-cell proteomics analysis using a norbornene probe to detect cysteine sulfenic acid in live HeLa cells. Comparison of the enriched proteins to those identified using dimedone and other <i>C</i>-nucleophilic probes revealed a complementary reactivity profile. Remarkably, 148 new members of the sulfenome were identified. These discoveries highlight how subtle differences in chemical reactivity of both the probes and cysteine residues influence detection. Overall, this study expands our understanding of protein oxidation at cysteine and reveals new proteins to consider for future studies of cysteine oxidation, redox regulation and signaling, and the biochemistry of oxidative stress. </p>

scholarly journals Hydrogen Peroxide: Small Molecule with Big Functions

Daxue Huaxue ◽  
2020 ◽  
Vol 0 (0) ◽  
pp. 3-0
Author(s):  
Houjin Li ◽  
Jinshan Li ◽  
Liuping Chen
Keyword(s):  
Hydrogen Peroxide ◽  
Small Molecule

scholarly journals Proteome-Wide Survey Reveals Norbornene Is Complementary to Dimedone and Related Nucleophilic Probes for Cysteine Sulfenic Acid

2019 ◽  
Author(s):  
Lisa Alcock ◽  
Maike Langini ◽  
Kai Stühler ◽  
Marc Remke ◽  
Michael Perkins ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Chemical Reactivity ◽  
Live Cells ◽  
Chemical Probes ◽  
Cysteine Oxidation ◽  
Sulfenic Acid ◽  
Proteomics Analysis ◽  
New Members ◽  
Specific Chemical ◽  
Future Studies

<p>Detection of cysteine sulfenic acid in live cells is critical in advancing our understanding of cysteine redox chemistry and its biological function. Accordingly, there is a need to develop sulfenic acid-specific chemical probes with distinct reaction mechanisms to facilitate proteome-wide detection of this important posttranslational modification. Herein, we report the first whole-cell proteomics analysis using a norbornene probe to detect cysteine sulfenic acid in live HeLa cells. Comparison of the enriched proteins to those identified using dimedone and other <i>C</i>-nucleophilic probes revealed a complementary reactivity profile. Remarkably, 148 new members of the sulfenome were identified. These discoveries highlight how subtle differences in chemical reactivity of both the probes and cysteine residues influence detection. Overall, this study expands our understanding of protein oxidation at cysteine and reveals new proteins to consider for future studies of cysteine oxidation, redox regulation and signaling, and the biochemistry of oxidative stress. </p>

scholarly journals Pathological hydrogen peroxide triggers the fibrillization of wild-type SOD1 via sulfenic acid modification of Cys-111

2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Wen-Chang Xu ◽  
Jin-Zhao Liang ◽  
Cheng Li ◽  
Zhi-Xin He ◽  
Han-Ye Yuan ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Wild Type ◽  
Sulfenic Acid ◽  
Acid Modification

scholarly journals Use of Dimedone-Based Chemical Probes for Sulfenic Acid Detection

2010 ◽  
pp. 95-115 ◽  
Author(s):  
Kimberly J. Nelson ◽  
Chananat Klomsiri ◽  
Simona G. Codreanu ◽  
Laura Soito ◽  
Daniel C. Liebler ◽  
...  
Keyword(s):  
Chemical Probes ◽  
Sulfenic Acid

scholarly journals Xanthine-Based Photoaffinity Probes Allow Assessment of Ligand Engagement by TRPC5 Channels

2020 ◽  
Author(s):  
Claudia Bauer ◽  
Aisling Minard ◽  
Isabelle Pickles ◽  
Matthew Burnham ◽  
Nikil Kapur ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Direct Evidence ◽  
Binding Mode ◽  
Chemical Probes ◽  
Binding Interaction ◽  
Biological Studies ◽  
Photoaffinity Probes ◽  
Direct Binding ◽  
Trpc5 Channels

TRPC1/4/5 cation channels are emerging drug targets for the treatment of, amongst others, central nervous system (CNS) disorders, kidney disease, and cardiovascular and metabolic disease. Various small-molecule TRPC1/4/5 modulators have been reported, including highly potent xanthine derivatives that can distinguish between specific TRPC1/4/5 tetramers. However, there is a paucity of information about their binding mode, which limits the ability to develop them further as chemical probes of specific TRPC1/4/5 channels for use in fundamental biological studies and drug discovery programmes. Here, we report the development of a set of potent xanthine-based photoaffinity probes that functionally mimic the xanthines Pico145 and AM237, respectively. Using these probes, we have developed a quantitative photoaffinity labelling protocol for TRPC5 channels. Our results provide the first direct evidence that xanthines modulate TRPC5 channels through a direct binding interaction with TRPC5 protein, and the first quantitative method for the assessment of binding interactions of TRPC5 and small molecules. Our method may allow the study of the mode-of-action of other TRPC1/4/5 modulators, and the identification of small molecule binding sites of TRPC1/4/5 channels.

scholarly journals Recent advances in the development of legumain-selective chemical probes and peptide prodrugs

2019 ◽  
Vol 400 (12) ◽  
pp. 1529-1550 ◽  
Author(s):  
Marcin Poreba
Keyword(s):  
Small Molecule ◽  
Molecular Target ◽  
Biological Processes ◽  
Chemical Probes ◽  
Moth Bean ◽  
Historical Perspectives ◽  
Asparaginyl Endopeptidase ◽  
Cellular Events ◽  
Leguminous Seeds ◽  
Extracellular Activity

Abstract Legumain, which is also known as vacuolar processing enzyme (VPE) or asparaginyl endopeptidase (AEP), is a cysteine protease that was first discovered and characterized in the leguminous seeds of the moth bean in the early 1990s. Later, this enzyme was also detected in higher organisms, including eukaryotes. This pH-dependent protease displays the highest activity in acidic endolysosomal compartments; however, legumain also displays nuclear, cytosolic and extracellular activity when stabilized by other proteins or intramolecular complexes. Based on the results from over 25 years of research, this protease is involved in multiple cellular events, including protein degradation and antigen presentation. Moreover, when dysregulated, this protease contributes to the progression of several diseases, with cancer being the well-studied example. Research on legumain biology was undoubtedly facilitated by the use of small molecule chemical tools. Therefore, in this review, I present the historical perspectives and most current strategies for the development of small molecule substrates, inhibitors and activity-based probes for legumain. These tools are of paramount importance in elucidating the roles of legumain in multiple biological processes. Finally, as this enzyme appears to be a promising molecular target for anticancer therapies, the development of legumain-activated prodrugs is also described.

scholarly journals Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

2020 ◽  
Vol 21 (20) ◽  
pp. 7549
Author(s):  
Paula Martín Moyano ◽  
Václav Němec ◽  
Kamil Paruch
Keyword(s):  
Clinical Trials ◽  
Protein Kinases ◽  
Small Molecule ◽  
Chemical Biology ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Chemical Probes ◽  
The Family

Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes.

The discovery of small molecule chemical probes of Bcl-XL and Mcl-1

2008 ◽  
Vol 16 (15) ◽  
pp. 7443-7449 ◽  
Author(s):  
Michael Prakesch ◽  
Alexey Yu Denisov ◽  
Marwen Naim ◽  
Kalle Gehring ◽  
Prabhat Arya
Keyword(s):  
Small Molecule ◽  
Chemical Probes
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