Dataset Information

Traceless peptide and protein modification via rational tuning of halopyridiniums

ABSTRACT: Building on the insights gained from systematically investigating of aromatic nucleophilic substitution (SNAr) and thiol-exchange, we identified the highly electron-deficient halopyridiniums as a tunable and predictable reaction platform for adjusting electrophilicity and thiol-cleavability by following a positive Hammett correlation. This pyridinium-based platform was practical for both cleavable peptide stapling and protein functionalization. With this highly tunable and predictable toolkit, we successfully achieved GSH-response cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, and proteome labeling. Furthermore, the positively charged species exhibit improved cell-permeability and digestion-stability, making them attractive candidates for the manipulation of the functions and biophysical properties of biomolecules.

ORGANISM(S): Homo Sapiens

SUBMITTER: Rui Wang

PROVIDER: PXD045683 | iProX | Mon Sep 25 00:00:00 BST 2023

REPOSITORIES: iProX

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Publications

Traceless Peptide and Protein Modification via Rational Tuning of Pyridiniums.

Wan Chuan C Zhang Yichi Y Wang Jinpeng J Xing Yun Y Yang Dongyan D Luo Qinhong Q Liu Jianbo J Ye Yuxin Y Liu Zhihong Z Yin Feng F Wang Rui R Li Zigang Z

Journal of the American Chemical Society 20240119 4

Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This platform offers highly tunable and predictable conjugation and cleavage by rationally estimating the electron effect on the nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, and proteome labeling were achieved based on this facile pyridinium-thiol-exchange protocol. ...[more]

PMID: 38239111

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Project description:Given the clinical need for osteoregenerative materials incorporating controlled biomimetic and biophysical cues, a novel norbornene-modified gelatin was developed with a degree of substitution of 169% compared to the number of amines present in pristine gelatin type B. It is, to the best of our knowledge, the highest substitution degree reported to date for norbornene-functionalised gelatin. Thiol-ene crosslinking exploiting thiolated gelatin as cell-interactive crosslinker resulted in networks with high (>95%) norbornene conversion. Comparing the number of physical crosslinks present, the degree of hydrolytic degradation upon modification, the network density as well as the chemical crosslinking type, the novel thiol-ene network was benchmarked against conventional gelatin-based systems in terms of the effect of biophysical cues, more specifically visco-elastic and topographical properties, affecting osteogenesis both in 2D and in 3D via a biofabrication strategy. The novel thiol-ene network outperformed conventional gelatin-based networks in terms of osteogenesis, as evidenced in 2D dental pulp stem cell seeding assays, resulting from the presentation of both a local (substrate elasticity, 25-40 kPa) and a bulk (compressive modulus, 25-45 kPa) osteogenic substrate modulus in combination with adequate fibrillar cell adhesion spacing to optimally transfer traction forces from the fibrillar ECM (as evidenced by mesh size determination with the rubber-elasticity theory) and resulting in a 1.5- and 1.7-fold increase in alkaline phosphatase activity and calcium production respectively as osteogenic markers (compared to the gold standard gelatin methacryloyl (GelMA)). Dental pulp stem cell encapsulation in extrusion-based biofabricated 3D constructs also showed a favorable response towards the novel thiol-ene network thanks to the combination of its RGD mobility (as observed from proteomic analysis), stress relaxation and substrate rigidity (bulk compressive modulus of 11-30 kPa) to enable a 1.5- and 7-fold increase in alkaline phosphatase activity and calcium production respectively as osteogenic markers (compared to the gold standard GelMA).

Dataset Information

Traceless peptide and protein modification via rational tuning of halopyridiniums

Publications

Traceless Peptide and Protein Modification via Rational Tuning of Pyridiniums.

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