Fast and Selective Cysteine Conjugation Using para-Quinone Methides

Organic Letters, Год журнала: 2024, Номер 26(41), С. 8951 - 8955

Опубликована: Окт. 7, 2024

An efficient and selective method for cysteine conjugation utilizing

Язык: Английский

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Chromophore Optimization in Organometallic Au(III) Cys Arylation of Peptides and Proteins for 266 nm Photoactivation

Опубликована: Июнь 11, 2024

Cysteine is the most reactive naturally occurring amino acid due to presence of a free thiol, presenting tantalizing handle for covalent modification peptides/proteins. Although many mass spectrometry experiments could benefit from site-specific Cys, utility direct arylation has not been thoroughly explored. Recently, Spokoyny and coworkers reported Au(III) organometallic reagent that robustly arylates Cys tolerates wide variety solvents conditions. Given chromophoric nature aryl groups known susceptibility carbon-sulfur bonds photodissociation, we set out identify an group efficiently cleave at 266 nm. A streamlined workflow was developed facilitate rapid examination large number aryls with minimal sample using simple test peptide, RAAACGVLK. We were able several yield abundant homolytic photodissociation adjacent short activation times (<10 ms). In addition, characterized radical products created by subjecting product ions further collisional activation. Finally, tested human hemoglobin, identified reaction conditions efficient intact proteins, evaluated photochemistry these ions.

Язык: Английский

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Copper(II)-mediated N-terminal modification of proteins with maleimide derivatives

Опубликована: Июнь 20, 2024

Maleimide derivatives are privileged reagents for the chemical modification of proteins via Michael addition cysteine due to their selectivity, reaction rate, and commercial availability. Since accessible free is rarely found in natural proteins, an alternative target maleimide highly desirable direct bioconjugation. In this study, we developed a copper(II)-mediated [3+2] cycloaddition with 2-pyridinecarboxaldehyde (2-PC) as operationally simple powerful method N-terminal peptides proteins. This utilizes commercially available maleimides attach diverse functionalities various amino acids. The combined use copper(II) ions heteroaromatic aldehydes key selective formation azomethine intermediates at N-terminus aqueous media under mild conditions, achieving high selectivity. We demonstrate preparation ternary protein complex cross-linked N-termini dually modified trastuzumab equipped monomethyl auristatin E (MMAE), cytotoxic agent, Cy5 fluorophore (MMAE–Cy5–trastuzumab). MMAE–Cy5–trastuzumab retained human epidermal growth factor receptor 2 (HER2) recognition activity exerted cytotoxicity against HER2-positive cells. Furthermore, helped successfully visualize cancer cells mouse tumors. straightforward will enhance accessibility utility conjugates defined structures across spectrum researchers.

Язык: Английский

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In situ Generation of Quinoliziniums for Dual Visible Light‐induced Gold(III)‐catalyzed Alkynylation and Peptide Modification

Asian Journal of Organic Chemistry, Год журнала: 2024, Номер 13(11)

Опубликована: Авг. 16, 2024

Abstract A new approach of dual visible light‐induced gold(III)‐catalyzed alkynylation and its application in selective modification alkyne‐linked peptides has been developed. The bis‐cyclometalated gold(III) complex exhibited roles (1) situ generation quinolizinium‐based photosensitizer (λ em =500 – 594 nm) (2) iminium ions. Under optimized conditions, alkynylated products were afforded good yields up to 73 %. this strategy gave modified 67 % conversion. Our light/gold(III) catalysis exemplifies the potential merging photocatalysis transition metal develop novel bioconjugation.

Язык: Английский

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Chemo-selective modification of cysteine residue: synthesis and application in the discovery of potential drug candidates

Опубликована: Сен. 6, 2024

Chemo-select modification of peptides, targeting a handful the most reactive proteinogenic amino acids (AAs), is gradually utilized to address medical needs peptide drugs and biopharmaceuticals. Cysteine (Cys), one less abundant AAs in many biological proteins, plays vital role catalysis, signal transduction, redox regulation gene expression. In natural (α-AAs) residues, Cys exhibits high nucleophilicity low redox-active potential, making it primary target for site-selective conjugation. This review summarizes several representative Cys-peptide/protein conjugation strategies developed recent years, including polar reactions, radical coupling stapling techniques.

Язык: Английский

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Heterotelechelic Organometallic PEG Reagents Enable Modular Access to Complex Bioconjugates

ACS Macro Letters, Год журнала: 2024, Номер 13(11), С. 1551 - 1557

Опубликована: Окт. 31, 2024

Organometallic oxidative addition complexes (OACs) have recently emerged as a powerful class of reagents for the rapid and chemoselective modification biomolecules. Notably, steric electronic properties ligand aryl group can be modified to tune kinetic profile reaction permit regioselective S-arylation. Using developed dicyclohexylphosphine-based bidentate P,N-ligated Au(III) OACs, we computationally experimentally examined effects sterically bulky electron deficient substrates achieve selective With this mechanistic insight, based on 4-iodoanisole 3,5-dimethyl-4-iodoanisole were incorporated end groups generate heterotelechelic bis-Au(III) poly(ethylene glycol) (PEG). This reagent performed S-arylation with model biomolecule, designed ankyrin repeat protein (DARPin), form protein–polymer OAC in situ. mediated second biologically relevant thiolated small molecules (metal chelator, saccharide, fluorophore) macromolecules (polymer therapeutic peptide). It is envisioned that approach could utilized construction biomacromolecular heteroconjugates S-aryl linkages.

Язык: Английский

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Dual-Performing Vinyltetrazine for Rapid, Selective Bioconjugation and Functionalization of Cysteine Proteins

ACS Chemical Biology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 21, 2024

Although methods for Cys-specific bioconjugation and functionalization of proteins have been developed widely utilized in biomolecule engineering therapeutic development, reagents this purpose are generally designed to accomplish only. Consequently, additional clickable groups must be attached these functionalization. Herein, we describe a new, simple, dual-performing bioconjugation–functionalization reagent, VMeTz, which possesses an electron-withdrawing tetrazine (Tz) substituted vinyl (V) moiety serve as both Michael receptor selective conjugation with Cys site click TCO derivatives introduce functionality. Critically, VMeTz contains methyl group that prevents the formation multiple Tz-containing Cys-adducts. Reactions Cys-containing peptides vitro live cells produce single stable adducts high selectivity. Moreover, Cys-VMeTz peptide protein conjugates undergo facile reactions TCO-functionalized labeling profiling. Furthermore, selectively activates delivers TCO-caged toxic substances Dox PROTAC ARV-771 cancer effects comparable those parent drugs. Collectively, studies demonstrate is useful reagent therapeutically significant

Язык: Английский

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Chromophore Optimization in Organometallic Au(III) Cys Arylation of Peptides and Proteins for 266 nm Photoactivation

Analytical Chemistry, Год журнала: 2024, Номер 96(36), С. 14581 - 14589

Опубликована: Авг. 28, 2024

Cysteine is the most reactive naturally occurring amino acid due to presence of a free thiol, presenting tantalizing handle for covalent modification peptides/proteins. Although many mass spectrometry experiments could benefit from site-specific Cys, utility direct arylation has not been thoroughly explored. Recently, Spokoyny and co-workers reported Au(III) organometallic reagent that robustly arylates Cys tolerates wide variety solvents conditions. Given chromophoric nature aryl groups known susceptibility carbon–sulfur bonds photodissociation, we set out identify an group efficiently cleave at 266 nm. A streamlined workflow was developed facilitate rapid examination large number aryls with minimal sample using simple test peptide, RAAACGVLK. We were able several yield abundant homolytic photodissociation adjacent short activation times (<10 ms). In addition, characterized radical products created by subjecting product ions further collisional activation. Finally, tested human hemoglobin, identified reaction conditions efficient intact proteins, evaluated photochemistry these ions.

Язык: Английский

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Organometallic Chemistry Tools for Building Biologically Relevant Nanoscale Systems

Journal of the American Chemical Society, Год журнала: 2024, Номер unknown

Опубликована: Окт. 29, 2024

The recent emergence of organometallic chemistry for modification biomolecular nanostructures has begun to rewrite the long-standing assumption among practitioners that small-molecule organometallics are fundamentally incompatible with biological systems. This Perspective sets out clarify some existing misconceptions by focusing on growing toolbox modification. Specifically, we highlight key transformations in constructing complex biologically relevant systems nanomolecular scale, and synthesis hybrid nanomaterials composed classical nanomaterial components combined species. As research progresses, many challenges associated applying this context rapidly being reassessed. Looking future, utility will likely make them more ubiquitous construction nanostructures.

Язык: Английский

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