constructing-cyclic-peptides-using-an-on-tether-sulfonium-center

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

In recent years, cyclic peptides have attracted increasing attention in the field of drug discovery due to their excellent biological activities, and, as ...

Shenzhen Bay laboratory

Peking University Shenzhen Graduate School

We report a facile thiol-yne type reaction triggered by the sulfonium center. After facile propargylation of thiolethers, the resulting sulfonium could undergo facile addition with thiols in aqueous media at ambient temperature. Further applying this reaction in unprotected peptides bearing neighboring methionine and cysteine could enable a facile intramolecular addition to construct cyclic peptides with better stability, good glutathione resistance, and increased cellular uptakes. Also, the propargylated sulfonium may be used as robust and versatile probes to target cysteines containing biomolecules.

A Sulfonium Triggered Thiol-yne Reaction for Cysteine Modification.

A novel amidation strategy using electrophilic sulfonium, which is soluble and stable in aqueous conditions, was developed. The sulfoniums could activate thioacid and carboxyl acid to efficiently react with amines to afford amides. This method enables applications in amidation in both aqueous media and solid-phase peptide synthesis, peptide/protein modifications, and reactive lysines of a proteome at pH 10 with activity-based protein profiling. A peptide ligand-directed labeling of the USP7-UBL2 domain was also performed using this method.

Electrophilic Sulfonium-Promoted Peptide and Protein Amidation in Aqueous Media.

The diversity of cyclic peptides was expanded by elaborating Mitsunobu macrocyclization, tethering various hydroxy acid building blocks with different N-amine substituents. This new strategy was then applied in synthesizing peptidomimetic estrogen receptor modulator (PERM) analogs on the solid support. The PERM analogs exhibited increased serum peptidase stability, cell penetration, and estrogen receptor α binding affinity. Studying diversity-oriented methods for preparing azacyclopeptides provides a new tool for macrocycle construction and further structural information for optimizing ERα modulators for ER positive breast cancers.

Diversity-Oriented Synthesis of ERα Modulators via Mitsunobu Macrocyclization.

Inhibition of amyloid-β peptide (Aβ) aggregation is a promising therapeutic strategy for Alzheimer's disease (AD), as Aβ aggregation is generally believed to trigger AD pathology. Pre-fibril Aβ-oligomers induce membrane disruption and are crucial to neurotoxicity. We have previously designed a short peptide called cyclic helical amyloid surface inhibitor (cHASI) that can selectively bind to the Aβ fibril surface. Here, we use cHASI to efficiently inhibit the surface-catalysed secondary nucleation process of Aβ in a lipid membrane environment. By incubating Aβ monomers with lipid vesicles, we show that during the assembly of Aβ into amyloid fibrils, oligomers are formed that markedly disrupt the lipid bilayer. Remarkably, when Aβ monomers are incubated with cHASI, although Aβ forms amyloid fibrils via primary nucleation and elongation, this pathway to fibrils does not damage the lipid bilayer. This indicates that only oligomers produced during secondary surface nucleation disrupt membrane integrity. The protective effect of cHASI is confirmed by cytotoxicity assays. Our study highlights the therapeutic potential for inhibiting the secondary nucleation process in Aβ aggregation, rather than inhibiting all pathways to fibril formation.

Therapeutic potential for amyloid surface inhibitor: only amyloid-β oligomers formed by secondary nucleation disrupt lipid membrane integrity.

Histidine (His, H) undergoes various post-translational modifications (PTMs) and plays multiple roles in protein interactions and enzyme catalyzed reactions. However, compared with other amino acids such as Lys or Cys, His modification is much less explored. Herein we describe a novel visible-light-driven thioacetal activation reaction which enables facile modification on histidine residues. An efficient addition to histidine imidazole N3 under biocompatible conditions was achieved with an electrophilic thionium intermediate. This method allows chemo-selective modification on peptides and proteins with good conversions and efficient histidine-proteome profiling with cell lysates. 78 histidine containing proteins were for the first time found with significant enrichment, most functioning in metal accumulation in brain related diseases. This facile His modification method greatly expands the chemo-selective toolbox for histidine-targeted protein conjugation and helps to reveal histidine's role in protein functions.

Article	Year
A Sulfonium Triggered Thiol-yne Reaction for Cysteine Modification. The Journal of organic chemistry\| PubMed ID: 31899633
Electrophilic Sulfonium-Promoted Peptide and Protein Amidation in Aqueous Media. Organic letters\| PubMed ID: 34968069	2022
Diversity-Oriented Synthesis of ERα Modulators via Mitsunobu Macrocyclization. Organic letters\| PubMed ID: 35546524	2022
Therapeutic potential for amyloid surface inhibitor: only amyloid-β oligomers formed by secondary nucleation disrupt lipid membrane integrity. The FEBS journal\| PubMed ID: 35670622	2022
Histidine-specific bioconjugation visible-light-promoted thioacetal activation. Chemical science\| PubMed ID: 35919717	2022

Chenshan Lian

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