Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels

Rochet, Léa N. C.; Bahou, Calise; Wojciechowski, Jonathan P.; Koutsopetras, Ilias; Britton, Phyllida; Spears, Richard J.; Thanasi, Ioanna A.; Shao, Baihao; Zhong, Lisha; Bučar, Dejan-Krešimir; Aliev, Abil E.; Porter, Michael J.; Stevens, Molly M.; Baker, James R.; Chudasama, Vijay

doi:10.1039/d3sc04976k

Chem. Sci.

2023

DOI: 10.1039/d3sc04976k

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Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels

Léa N. C. Rochet,

Calise Bahou,

Jonathan P. Wojciechowski

et al.

Abstract: Substituted pyridazinediones (PDs) enable reversible and tuneable cysteine modification with exemplification on peptides, proteins and hydrogels.

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2024

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Cited by 4 publications

References 75 publications

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Spring Expanding-like Polarity Reversal in Photoelectrochemical Biosensing

Jiang,

Xi,

Deng

et al. 2024

Anal. Chem.

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Although polarity-reversal photoelectrochemical (PEC) analysis can effectively eliminate false-positive and negative signals caused by interferents, achieving high sensitivity and accuracy is still a challenge. Hence, a spring expanding-like polarity reversal strategy with bipolar signal synergistic amplification is first proposed to help build a high-performance PEC analysis system. In this study, L-cysteine (L-cys) is discovered to not only act as a polarity regulator to elaborately reverse photocurrent via its covalent bond to Cu and Bi but also provide a relatively stable electron donor to effectively consume the photogenerated holes compared with commonly used H 2 O 2 and ascorbic acid. More importantly, the amino and electron-rich functional acridine groups in the dye acriflavine endow an electrochemical activity to accelerate electron transfer between the electrode and solution, thus enabling bipolar synergistic signal amplification for acquiring an extremely enlarged photocurrent variation that is of great significance to overcome the rigorous signal prereversal depression and reversal amplification in traditional polarity-reversal systems. Accordingly, the PEC biosensor with the proposed spring expanding-like polarity reversal strategy exhibits excellent sensitivity and accuracy, reflecting ultralow detection limits of 0.04 fM toward lead ions (Pb 2+ ) and good anti-interference ability in the detection of natural water samples. This work provides an avenue for exploring a new polarity reversal strategy for accomplishing highperformance PEC bioanalysis, expected to be widely applied in environmental monitoring, clinical diagnosis, and food supervision.

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Spring Expanding-like Polarity Reversal in Photoelectrochemical Biosensing

Jiang,

Xi,

Deng

et al. 2024

Anal. Chem.

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

Chang,

Xu,

Dong

et al. 2024

ACS Chem. Biol.

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

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Selective pH-Responsive Conjugation between a Pair of De Novo Discovered Peptides

Ohno,

Vinogradov,

Suga

2024

J. Am. Chem. Soc.

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There is a demand for site-selective peptide/protein conjugation chemistry that is fully reversible in a stimulusresponsive manner. The contemporary methods for site-selective protein modification enable the preparation of homogeneous protein−small molecule conjugates, which are indispensable for drug delivery and chemical biology purposes, but such chemistries are usually irreversible. In contrast, the existing reversible protein labeling techniques are generally not site-selective. Here, we report an mRNA display-enabled de novo discovery of a pair of peptides which selectively react with each other to form a conjugate that is stable under neutral conditions (pH 7.5) but rapidly dissociates into the constituents at pH 10. A Cys thiol of peptide CP1 rapidly reacts (k 1 = 340 M −1 •s −1 ) with the isothiocyanate moiety in partner ITC6 to furnish a stable dithiocarbamate (t 1/2 = 6 h at pH 7.5). We show that the pH-responsive nature of the reaction (conjugate's t 1/2 = 5 min at pH 10) can be leveraged to utilize ITC6 (1) as a pull-down handle to selectively isolate CP1 from cell lysates and (2) as a temporary protecting group to protect CP1 from nonspecific Cys labeling reagents such as iodoacetamide. Altogether, the chemistry developed here complements the existing approaches and is applicable in a variety of chemical biology settings where selective reversible reactions are needed.

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Use of pyridazinediones for tuneable and reversible covalent cysteine modification applied to peptides, proteins and hydrogels

Abstract: Substituted pyridazinediones (PDs) enable reversible and tuneable cysteine modification with exemplification on peptides, proteins and hydrogels.

Cited by 4 publications

References 75 publications

Spring Expanding-like Polarity Reversal in Photoelectrochemical Biosensing

Spring Expanding-like Polarity Reversal in Photoelectrochemical Biosensing

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

Selective pH-Responsive Conjugation between a Pair of De Novo Discovered Peptides

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