Discovery of Heteroaromatic Sulfones As a New Class of Biologically Compatible Thiol-Selective Reagents

Chen, Xiaofei; Wu, Hanzhi; Park, Chung‐Min; Poole, Thomas H.; Keceli, Gizem; Devarie‐Baez, Nelmi O.; Tsang, Allen W.; Lowther, W. Todd; Poole, Leslie B.; King, S. Bruce; Xian, Ming; Furdui, Cristina M.

doi:10.1021/acschembio.7b00444

Cited by 43 publications

(46 citation statements)

References 40 publications

(100 reference statements)

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“…Inspired by these studies, we developed a chemoproteomic platform to measure the ability of H 2 O 2 to affect thiol reactivity toward an electrophilic iodoacetamide-alkyne probe (IPM) in native cell proteomes. We chose a relatively low concentration of IPM (100 M) for thiol labeling in that a high mM concentration of thiol alkylating reagents can also react with oxidized forms of cysteines (36,37). Moreover, it has been well-demonstrated that 100 M of iodoacetamide-based reagent is able to completely label the native free thiol proteome (10, 38 -43).…”

Section: Resultsmentioning

confidence: 99%

Systematic and Quantitative Assessment of Hydrogen Peroxide Reactivity With Cysteines Across Human Proteomes

Liu

Sun

et al. 2017

Molecular & Cellular Proteomics

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Protein cysteinyl residues are the mediators of hydrogen peroxide (HO)-dependent redox signaling. However, site-specific mapping of the selectivity and dynamics of these redox reactions in cells poses a major analytical challenge. Here we describe a chemoproteomic platform to systematically and quantitatively analyze the reactivity of thousands of cysteines toward HO in human cells. We identified >900 HO-sensitive cysteines, which are defined as the HO-dependent redoxome. Although redox sites associated with antioxidative and metabolic functions are consistent, most of the HO-dependent redoxome varies dramatically between different cells. Structural analyses reveal that HO-sensitive cysteines are less conserved than their redox-insensitive counterparts and display distinct sequence motifs, structural features, and potential for crosstalk with lysine modifications. Notably, our chemoproteomic platform also provides an opportunity to predict oxidation-triggered protein conformational changes. The data are freely accessible as a resource at http://redox.ncpsb.org/OXID/.

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Section: Resultsmentioning

confidence: 99%

Systematic and Quantitative Assessment of Hydrogen Peroxide Reactivity With Cysteines Across Human Proteomes

Liu

Sun

et al. 2017

Molecular & Cellular Proteomics

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“…[82] Xian and Furdui developed an ew heteroaromatic alkylsulfone,4 -(5-methanesulfonyl- [1,2,3,4]tetrazol-1-yl)-phenol (MSTP), for the selective blocking of protein thiols without crossreaction with sulfenic acids. [83] Theh igh thiol-specificity of these sulfone reagents was further highlighted in selective modifications of complex molecules,s uch as polyacrylamide hydrogels [84] and protein enzymes. [85] Methylsulfone-based arylation reagents were also developed for thiol conjugation in living cells.I n2 016, Fang reported 4-methylsulfonyl-N-n-1,8-naphthalimide (MSBN) as Figure 6.…”

Section: Heteroaryl Methylsulfones For Cysteine Arylationmentioning

confidence: 99%

Arylation Chemistry for Bioconjugation

et al. 2019

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Bioconjugation chemistry has been used to prepare modified biomolecules with functions beyond what nature intended. Central to these techniques is the development of highly efficient and selective bioconjugation reactions that operate under mild, biomolecule compatible conditions. Methods that form a nucleophile–sp2 carbon bond show promise for creating bioconjugates with new modifications, sometimes resulting in molecules with unparalleled functions. Here we outline and review sulfur, nitrogen, selenium, oxygen, and carbon arylative bioconjugation strategies and their applications to modify peptides, proteins, sugars, and nucleic acids

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“…A similar unreported compound MMV272144 ( 426 ) is featured in the Pathogen Box. However it shares structural homology with MSTP ( 427 ), which was found to selectively react with protein thiols …”

Section: Tuberculosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Discovery of Heteroaromatic Sulfones As a New Class of Biologically Compatible Thiol-Selective Reagents

Cited by 43 publications

References 40 publications

Systematic and Quantitative Assessment of Hydrogen Peroxide Reactivity With Cysteines Across Human Proteomes

Systematic and Quantitative Assessment of Hydrogen Peroxide Reactivity With Cysteines Across Human Proteomes

Arylation Chemistry for Bioconjugation

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

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