Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(12), P. 5673 - 5724

Published: Dec. 19, 2018

Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is predominant strategy in TCI development. The recent ascent drugs has stimulated considerable efforts characterize alternative warheads for covalent-reversible irreversible engagement as well acids. This Perspective article provides an overview warheads-beyond amides-recently used design targeted ligands. Promising groups that have not yet demonstrated their utility development also highlighted. Special emphasis placed on discussion reactivity case studies illustrating applications medicinal chemistry chemical biology.

Language: Английский

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Advances in covalent drug discovery

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(12), P. 881 - 898

Published: Aug. 25, 2022

Language: Английский

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Chemistry for Covalent Modification of Endogenous/Native Proteins: From Test Tubes to Complex Biological Systems

Journal of the American Chemical Society, Journal Year: 2018, Volume and Issue: 141(7), P. 2782 - 2799

Published: Dec. 28, 2018

Chemical modification of proteins provides powerful tools to realize a broad range exciting biological applications, including the development new classes biopharmaceuticals and functional studies individual in complex systems. Numerous strategies for linking desired chemical probes with target have been developed last two decades, most exploiting genetic protein engineering and/or bio-orthogonal chemistry that utilizes unnatural amino acids incorporated into proteins. Modification native test tubes contexts by site-specific target-selective approaches remains challenging because appropriate organic carry out such modifications is currently limited. Nonetheless, variety promising appeared recently address this grand challenge biology. These chemistries yield protein-based well-defined bioconjugations, specific labeling endogenous various crude milieus, establishment proteomics as research area science. In Perspective, we focus on recent remarkable progress modification. We survey characteristics methods describe briefly these advanced applications unsolved issues. Current limitations future directions field are also discussed.

Language: Английский

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A proteome-wide atlas of lysine-reactive chemistry

Nature Chemistry, Journal Year: 2021, Volume and Issue: 13(11), P. 1081 - 1092

Published: Sept. 9, 2021

Language: Английский

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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

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Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(40), P. 16377 - 16382

Published: Oct. 1, 2021

The targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current proteolysis-targeting chimera (PROTAC) methodology. We herein report a covalent nanobody-based PROTAC strategy, termed GlueTAC, protein high specificity efficiency. first established mass-spectrometry-based screening platform rapid development nanobody (GlueBody) allowed proximity-enabled cross-linking surface antigens on cancer cells. By conjugation cell-penetrating peptide lysosomal-sorting sequence, resulting GlueTAC triggered internalization programmed death-ligand 1 (PD-L1), which provides new avenue to target degrade cell-surface proteins.

Language: Английский

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Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Cell chemical biology, Journal Year: 2019, Volume and Issue: 26(11), P. 1486 - 1500

Published: Oct. 17, 2019

Language: Английский

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Reversible lysine-targeted probes reveal residence time-based kinase selectivity

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(9), P. 934 - 941

Published: May 19, 2022

Language: Английский

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Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

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In Vivo Applications of Bioorthogonal Reactions: Chemistry and Targeting Mechanisms

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(20)

Published: Jan. 19, 2023

Bioorthogonal chemistry involves selective biocompatible reactions between functional groups that are not normally present in biology. It has been used to probe biomolecules living systems, and advanced biomedical strategies such as diagnostics therapeutics. In this review, the challenges opportunities encountered when translating vitro bioorthogonal approaches vivo settings presented, with a focus on methods deliver reaction components. These include metabolic bioengineering, active targeting, passive simultaneously strategies. The suitability of ligation bond cleavage for applications is critically appraised, practical considerations optimum scheduling regimen pretargeting discussed. Finally, we our own perspectives area identify what, view, key must be overcome maximise impact these approaches.

Language: Английский

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