Potent Inhibition and Rapid Photoactivation of Endogenous Bruton’s Tyrosine Kinase Activity in Native Cells via Opto-Covalent Modulators DOI

Weizhi Weng,

Yanping Zhang, Zhengying Pan

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(42), P. 28717 - 28727

Published: Oct. 10, 2024

Naturally, kinases exert their activities in a highly regulated fashion. A number of ingenious approaches have been developed to artificially control kinase activity by external stimuli, such as the incorporation unnatural amino acids or fusion additional protein domains; however, methods that directly modulate endogenous native cells are lacking. Herein, we present facile and potent method takes advantage recent developments targeted covalent inhibitors rapid light-mediated uncaging chemistry. Using an important drug target, Bruton's tyrosine (BTK), example, these opto-covalent modulators successfully blocked BTK after simple incubation washout steps. However, upon few minutes light irradiation, was cleanly restored, could be again conventional inhibitors. Promisingly, this photoactivation strategy easily worked human peripheral blood mononuclear (hPBMCs).

Language: Английский

Hybrid Small-Molecule/Protein Fluorescent Probes DOI
Masafumi Minoshima, Shahi Imam Reja,

Ryu Hashimoto

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(10), P. 6198 - 6270

Published: May 8, 2024

Hybrid small-molecule/protein fluorescent probes are powerful tools for visualizing protein localization and function in living cells. These hybrid constructed by diverse site-specific chemical labeling approaches through reactions to exogenous peptide/small tags, enzymatic post-translational modifications, bioorthogonal genetically incorporated unnatural amino acids, ligand-directed reactions. The employed imaging trafficking, conformational changes, bioanalytes surrounding proteins. In addition, facilitate visualization of dynamics at the single-molecule level defined structure with super-resolution imaging. this review, we discuss development bioimaging applications based on hybrids.

Language: Английский

Citations

26
Stimulated emission depletion microscopy DOI
Gražvydas Lukinavičius, Jonatan Alvelid, Rūta Gerasimaitė

et al.

Nature Reviews Methods Primers, Journal Year: 2024, Volume and Issue: 4(1)

Published: Aug. 8, 2024

Language: Английский

Citations

19
Targeted Covalent Modification Strategies for Drugging the Undruggable Targets DOI
Tomonori Tamura,

Masaharu Kawano,

Itaru Hamachi

et al.

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

Published: Jan. 7, 2025

The term "undruggable" refers to proteins or other biological targets that have been historically challenging target with conventional drugs therapeutic strategies because of their structural, functional, dynamic properties. Drugging such undruggable is essential develop new therapies for diseases where current treatment options are limited nonexistent. Thus, investigating methods achieve drugging an important challenge in medicinal chemistry. Among the numerous methodologies drug discovery, covalent modification has emerged as a transformative strategy. attachment diverse functional molecules provides powerful platform creating highly potent and chemical tools well ability provide valuable information on structures dynamics targets. In this review, we summarize recent examples biomolecules development therapeutics overcome discovery challenges highlight how contribute toward particular, focus use chemistry drugs, identification, screening, artificial modulation post-translational modifications, cancer specific chemotherapies, nucleic acid-based therapeutics.

Language: Английский

Citations

1
The expanding repertoire of covalent warheads for drug discovery DOI
Namrashee V. Mehta, Mariam S. Degani

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103799 - 103799

Published: Oct. 13, 2023

Language: Английский

Citations

22
Protein–protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies DOI Creative Commons
Bobby Lucero, Karol R. Francisco,

Lawrence J. Liu

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(7), P. 474 - 488

Published: May 30, 2023

The development of small-molecule inhibitors or stabilizers selected protein–protein interactions (PPIs) interest holds considerable promise for the research tools as well candidate therapeutics. In this context, covalent modification residues within target protein has emerged a promising mechanism action to obtain modulators PPIs with appropriate selectivity and duration action. Different labeling strategies are now available that can potentially allow rational, ground-up discovery optimization ligands PPI stabilizers. This review article provides synopsis recent developments applications such tactics, particular focus on site-directed fragment tethering proximity-enabled approaches.

Language: Английский

Citations

16
Design and application of a fluorescent probe for imaging of endogenous Bruton’s tyrosine kinase with preserved enzymatic activity DOI Creative Commons

Anna P. Valaka,

Helena Filipsson Nyström, Liliana Håversen

et al.

RSC Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Development of a novel fluorescent probe for endogenous BTK imaging using evobrutinib as scaffold. Evo-2 enabled real-time visualisation dynamics in living cells while preserving its enzymatic activity.

Language: Английский

Citations

0
N-Acyl-N-alkyl/aryl Sulfonamide Chemistry Assisted by Proximity for Modification and Covalent Inhibition of Endogenous Proteins in Living Systems DOI
Tomonori Tamura, Itaru Hamachi

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

ConspectusSelective chemical modification of endogenous proteins in living systems with synthetic small molecular probes is a central challenge biology. Such has variety applications important for biological and pharmaceutical research, including protein visualization, functionalization, proteome-wide profiling enzyme activity, irreversible inhibition activity. Traditional chemistry selective cells largely relies on the high nucleophilicity cysteine residues to ensure target-selectivity site-specificity modification. More recently, lysine residues, which are more abundant surfaces, have attracted attention covalent proteins. However, it been difficult efficiently modify ε-amino groups side-chains, mostly (∼99.9%) protonated thus exhibit low at physiological pH. Our group revealed that

Language: Английский

Citations

3
Ligand-directed covalent labelling of adenosine receptors DOI Creative Commons

C. Li,

Karen J. Gregory,

Manuela Jörg

et al.

Purinergic Signalling, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Language: Английский

Citations

0
Chemical biology tools for protein labelling: insights into cell–cell communication DOI Creative Commons
Megan H. Wright

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(18), P. 1445 - 1457

Published: Sept. 21, 2023

Multicellular organisms require carefully orchestrated communication between and within cell types tissues, many unicellular also sense their context environment, sometimes coordinating responses. This review highlights contributions from chemical biology in discovering probing mechanisms of cell–cell communication. We focus on tools for labelling proteins a cellular how these can be applied to decipher the target receptor signalling molecule, label interest situ understand its biology, provide read-out protein activity or interactions downstream pathways, discover protein–protein across interfaces.

Language: Английский

Citations

6
Fluoroalcohols for chemical modification of biomolecules DOI Creative Commons
Md. Nuruzzaman, Zeinab M. Nizam, Jun Ohata

et al.

Tetrahedron Chem, Journal Year: 2024, Volume and Issue: 11, P. 100088 - 100088

Published: Aug. 1, 2024

While their broad utility in various chemistry fields were well recognized for decades, fluoroalcohols have recently emerged as a unique solvent system bioconjugation development. This review describes examples and roles of such trifluoroethanol (TFE) hexafluoroisopropanol (HFIP) chemical modification biomolecules polypeptides, nucleic acids, saccharides. Many processes facilitated by notable functions those proton shuttle, reversible adduct formation with reactive species, compatibility electrochemistry/photochemistry. The usefulness the fluoroalcohol solvents can be even promoted its combination different reaction enhancement protein stabilization. collection transformations this is an indication rapid growth solvent-assisted field.

Language: Английский

Citations

0