Dataset Information

Thionoesters: A Native Chemical Ligation-Inspired Approach to Cysteine-Triggered H2S Donors.

ABSTRACT: Native chemical ligation (NCL) is a simple, widely used, and powerful synthetic tool to ligate N-terminal cysteine residues and C-terminal ?-thioesters via a thermodynamically stable amide bond. Building on this well-established reactivity, as well as advancing our interests in the chemical biology of reactive sulfur species including hydrogen sulfide (H2S), we hypothesized that thionoesters, which are constitutional isomers of thioesters, would undergo a similar NCL reaction in the presence of cysteine to release H2S under physiological conditions. Herein, we report mechanistic and kinetic investigations into cysteine-mediated H2S release from thionoesters. We found that this reaction proceeds with high H2S-releasing efficiency (?80%) and with a rate constant (9.1 ± 0.3 M-1 s-1) comparable to that for copper-catalyzed azide-alkyne cycloadditions (CuAAC). Additionally, we found that the final product of the reaction of cysteine with thionoesters results in the formation of a stable dihydrothiazole, which is an iron-binding motif commonly found in siderophores produced by bacteria during periods of nutrient deprivation.

SUBMITTER: Cerda MM

PROVIDER: S-EPMC6504978 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Thionoesters: A Native Chemical Ligation-Inspired Approach to Cysteine-Triggered H<sub>2</sub>S Donors.

Cerda Matthew M MM Zhao Yu Y Pluth Michael D MD

Journal of the American Chemical Society 20180919 39

Native chemical ligation (NCL) is a simple, widely used, and powerful synthetic tool to ligate N-terminal cysteine residues and C-terminal α-thioesters via a thermodynamically stable amide bond. Building on this well-established reactivity, as well as advancing our interests in the chemical biology of reactive sulfur species including hydrogen sulfide (H<sub>2</sub>S), we hypothesized that thionoesters, which are constitutional isomers of thioesters, would undergo a similar NCL reaction in the p ...[more]

PMID: 30230325

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Project description:Oxo-ester mediated native chemical ligation (OMNCL) is a variation of the more general native chemical ligation (NCL) reaction that is widely employed for chemoselective ligation of peptide fragments. While OMNCL has been used for a variety of peptide ligations and for biomolecular modification of surfaces, it is typically practiced under harsh conditions that are unsuitable for use in a biological context. In this report we describe the use of OMNCL for polymer hydrogel formation, in-vitro cell encapsulation, and in-vivo implantation. Multivalent polymer precursors containing N-hydroxysuccinimide (NHS) activated oxo-esters and N-cysteine (N-Cys) endgroups were chemically synthesized from branched poly(ethylene glycol) (PEG). Hydrogels formed rapidly at physiologic pH upon mixing of aqueous solutions of NHS and N-Cys functionalized PEGs. Quantitative 1H NMR experiments showed that the reaction proceeds through an OMNCL pathway involving thiol capture to form a thioester intermediate, followed by an S-to-N acyl rearrangement to yield an amide cross-link. pH and temperature were found to influence gelation rate, allowing tailoring of gelation times from a few seconds to a few minutes. OMNCL hydrogels initially swelled before contracting to reach an equilibrium increase in relative wet weight of 0%. This unique behavior impacted the gel stiffness and was attributed to latent formation of disulfide cross-links between network-bound Cys residues. OMNCL hydrogels were adhesive to hydrated tissue, generating a lap shear adhesion strength of 46 kPa. Cells encapsulated in OMNCL hydrogels maintained high viability, and in-situ formation of OMNCL hydrogel by subcutaneous injection in mice generated a minimal acute inflammatory response. OMNCL represents a promising strategy for chemical cross-linking of hydrogels in a biological context and is an attractive candidate for in-vivo applications such as wound healing, tissue repair, drug delivery, and tissue engineering.

Dataset Information

Thionoesters: A Native Chemical Ligation-Inspired Approach to Cysteine-Triggered H2S Donors.

Publications

Thionoesters: A Native Chemical Ligation-Inspired Approach to Cysteine-Triggered H<sub>2</sub>S Donors.

Similar Datasets

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