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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Chemical and Enzymatic Methods for Post-Translational Protein–Protein Conjugation

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(32), P. 14404 - 14419

Published: Aug. 1, 2022

Fusion proteins play an essential role in the biosciences but suffer from several key limitations, including requirement for N-to-C terminal ligation, incompatibility of constituent domains, incorrect folding, and loss biological activity. This perspective focuses on chemical enzymatic approaches post-translational generation well-defined protein-protein conjugates, which overcome some limitations faced by traditional fusion techniques. Methods discussed range modification nucleophilic canonical amino acid residues to incorporation unnatural a methods, sortase-mediated ligation. Through summarizing progress this rapidly growing field, successes challenges associated with using are highlighted areas requiring further development discussed.

Language: Английский

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Development and Recent Advances in Lysine and N-Terminal Bioconjugation for Peptides and Proteins

Molecules, Journal Year: 2023, Volume and Issue: 28(3), P. 1083 - 1083

Published: Jan. 21, 2023

The demand for creation of protein diversity and regulation function through native modification post-translational has ignited the development selective chemical methods peptides proteins. Chemical bioconjugation offers functionalization providing bioconjugates with desired properties functions diverse applications in biology, medicine, biomaterials. amino group existing at lysine residue N-terminus proteins been extensively studied because its good nucleophilicity high surface exposure. Herein, we review groups on featuring excellent selectivity, mild reaction conditions, short time, conversion, biocompatibility, preservation integrity. This is organized based chemoselectivity site-selectivity reagents to acid residues aiming provide guidance selection appropriate methods.

Language: Английский

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Silicon-Containing Thiol-Specific Bioconjugating Reagent

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(3), P. 1776 - 1782

Published: Jan. 10, 2024

A new bioconjugation reagent containing silicon has been developed for the selective reaction with thiols. The inclusion of significantly improves chemoselectivity and suppresses retro processes, thereby exceeding capabilities traditional reagents. method is versatile compatible a broad range thiols unsaturated carbonyl compounds yields moderate to high results. These reactions can be conducted under biocompatible conditions, making them suitable protein bioconjugation. resulting conjugates display good stability in presence various biomolecules, which suggests their potential application synthesis antibody–drug conjugates. Furthermore, moiety within conjugated products opens up avenues drug release bridging inorganics other disciplines. This class silicon-containing thiol-specific reagents significant implications researchers working bioanalytical science medicinal chemistry leads innovative opportunities advancing field research chemistry.

Language: Английский

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Fast Cysteine Bioconjugation Chemistry

Chemistry - A European Journal, Journal Year: 2022, Volume and Issue: 28(66)

Published: Aug. 16, 2022

Cysteine bioconjugation serves as a powerful tool in biological research and has been widely used for chemical modification of proteins, constructing antibody-drug conjugates, enabling cell imaging studies. conjugation reactions with fast kinetics exquisite selectivity have under heavy pursuit they would allow clean protein just stoichiometric amounts reagents, which minimizes side reactions, simplifies purification broadens functional group tolerance. In this concept, we summarize the recent advances cysteine bioconjugation, discuss mechanism principles that underlie high efficiencies newly developed reactive reagents.

Language: Английский

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A simple method for developing lysine targeted covalent protein reagents

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 1, 2023

Abstract Peptide-based covalent probes can target shallow protein surfaces not typically addressable using small molecules, yet there is a need for versatile approaches to convert native peptide sequences into binders that broad range of residues. Here we report protein-based thio-methacrylate esters—electrophiles be installed easily on unprotected peptides and proteins via cysteine side chains, react efficiently selectively with lysine chains the target. Methacrylate phosphopeptides derived from 14-3-3-binding irreversibly label 14-3-3σ either or residues, depending position electrophile. targeting conserved residue exhibit pan-isoform binding 14-3-3 both in lysates extracellular media. Finally, apply this approach develop binders. A methacrylate-modified variant colicin E9 immunity binds DNAse, resulting significantly higher thermal stability relative non-covalent complex. Our offers simple route potent

Language: Английский

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Unlocking the Potential of Bio‐Based Nitrogen‐Rich Furanic Platforms as Biomass Synthons

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(28)

Published: May 5, 2023

Abstract The demand for new biomass‐derived fine and commodity chemicals propels the discovery of methodologies synthons. Whereas furfural 5‐hydroxymethylfurfural are cornerstones sustainable chemistry, 3‐acetamido‐5‐acetyl furan (3A5AF), an N ‐rich obtained from chitin biomass, remains unexplored, due to poor reactivity acetyl group relative previous furanic aldehydes. Here we developed a reactive 3‐acetamido‐5‐furfuryl aldehyde (3A5F) demonstrated utility this synthon as source bio‐derived nitrogen‐rich heteroaromatics, carbocycles, bioconjugation reagent.

Language: Английский

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Location-agnostic site-specific protein bioconjugation via Baylis Hillman adducts

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 29, 2024

Proteins labelled site-specifically with small molecules are valuable assets for chemical biology and drug development. The unique reactivity profile of the 1,2-aminothiol moiety N-terminal cysteines (N-Cys) proteins renders it highly attractive regioselective protein labelling. Herein, we report an ultrafast Z-selective reaction between isatin-derived Baylis Hillman adducts 1,2-aminothiols to form a bis-heterocyclic scaffold, employ stable bioconjugation under both in vitro live-cell conditions. We refer our technology as orchestrated aminothiol labelling (BHoPAL). Furthermore, lipoic acid ligase-based introducing at any desired site within proteins, rendering BHoPAL location-agnostic (not limited N-Cys). By using this approach tandem BHoPAL, generate dually bioconjugates appended different labels two distinct specific sites on single molecule. Taken together, toolkit that disclose herein will contribute towards generation mono multi-labelled protein-small molecule applications diverse biophysical assays, cellular imaging, production therapeutic protein-drug conjugates. In addition bioconjugation, scaffold find synthetic medicinal chemistry.

Language: Английский

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π-Clamp-Mediated Homo- and Heterodimerization of Single-Domain Antibodies via Site-Specific Homobifunctional Conjugation

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(29), P. 13026 - 13031

Published: July 14, 2022

Post-translational protein-protein conjugation produces bioconjugates that are unavailable via genetic fusion approaches. A method for preparing conjugates using π-clamp-mediated cysteine arylation with pentafluorophenyl sulfonamide functional groups is described. Two computationally designed antibodies targeting the SARS-CoV-2 receptor binding domain were produced (

Language: Английский

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A vinyl-decorated covalent organic framework for ferroptotic cancer therapy via visible-light-triggered cysteine depletion

Journal of Materials Chemistry B, Journal Year: 2022, Volume and Issue: 10(43), P. 8894 - 8909

Published: Jan. 1, 2022

Biothiols, including glutathione (GSH) and cysteine, are important reductants that maintain intracellular redox homeostasis. Recent studies have demonstrated cysteine deprivation is a more effective antitumor strategy than GSH depletion. However, the lack of highly chemoselective tumor-specific cysteine-consuming reagents limits practical application deprivation. Herein, we report vinyl-decorated nanoscale covalent organic framework (COF) prepared in aqueous solution at room temperature. After encapsulating Ru(II)-based photocatalyst, obtained Ru(II)@COF-V efficiently catalyzes thiol-ene click reaction between vinyl upon visible-light irradiation. preferentially accumulates lipid droplets tumor cells via raft- caveolin-related endocytosis induces peroxidation ferroptosis by consuming exhibiting powerful therapeutic activity against colon cancer. We believe this study both enriches ambient synthesis COFs highlights feasibility photochemical reactions for therapy.

Language: Английский

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