Aromatic capping surprisingly stabilizes furan moieties in peptides against acidic degradation

Abstract

We herein describe the synthesis of furan containing peptides for further post-synthetic derivatisation in solution through our recently developed furan-oxidation-labeling technology. Previously, it was reported by others that during acidic cleavage of furan-modified peptides, furan moieties can suffer from degradation. We demonstrate here that this degradation is position dependent and can be fully suppressed through introduction of proximate aromatic residues. Versatile introduction of 2-furylalanine at internal, C-terminal as well as the sensitive N-terminal positions has now been proven possible.

Pyrrolidinyl Peptide Nucleic Acid Probes Capable of Crosslinking with DNA: Effects of Terminal and Internal Modifications on Crosslink Efficiency

“…MALDI‐TOF MS analysis of the furan‐modified acpcPNA prepared by the standard on‐solid‐support post‐synthetic modification of the PNA by Pfp‐activated 3‐(2‐furyl)propionic acid, and subsequent TFA cleavage, showed extensive decomposition of the furan ring (Figure S5). Such acid sensitivity of the furan moiety has been well recognized, and methods to synthesize furan‐modified peptides or PNAs with the aim to prevent its decomposition have been proposed [24,26] . In 2017, a new protocol to synthesize furan‐modified PNA probes via the temporary protection of the furan moiety through the formation of a furan‐maleimide adduct was developed [25] .…”

“…Such acid sensitivity of the furan moiety has been well recognized, and methods to synthesize furan-modified peptides or PNAs with the aim to prevent its decomposition have been proposed. [24,26] In 2017, a new protocol to synthesize furan-modified PNA probes via the temporary protection of the furan moiety through the formation of a furan-maleimide adduct was developed. [25] However, this protocol requires extra protection-deprotection steps, and the subsequent deprotection by retro-Diels-Alder reactions requires a high temperature and a long reaction time.…”

A Photosensitized Singlet Oxygen (1O2) Toolbox for Bio-Organic Applications: Tailoring 1O2 Generation for DNA and Protein Labelling, Targeting and Biosensing

“…Within our research group, the photochemical furan-based oxidation technology described by K. Hoogewijs et al [ 138 ], has been applied for the ligation [ 106 ] and cyclisation [ 139 ] of peptides as well as the covalent trapping of protein–protein interactions [ 110 ]. In a peptide ligation strategy, furan was attached onto the C-terminus of one peptide and successfully ligated with a hydrazide containing peptide in the presence of light and RB as PS.…”

Exploiting furan's versatile reactivity in reversible and irreversible orthogonal peptide labeling

“…10 In a more recent contribution dealing with the site specific incorporation of furan at various positions in a peptide, we showed that these hurdles can be overcome by slightly adapting the reaction conditions. 11 Additionally, the recently reported procedure of Davis and coworkers for the Suzuki-Miyaura based introduction of furan onto genetically encoded aryl halides 12 opens the way to site-specific furan incorporation into proteins. These recent synthetic advances prompted us to explore furan's unique reactivity for biomolecular labeling and conjugation strategies involving peptides.…”

“…In conclusion, as the incorporation of furan moieties into peptides and proteins has recently been firmly established in various contexts (vide supra), 11,12 the current methodology ideally complements the toolbox of bio-orthogonal labeling reactions. In conjunction with our previously developed furan-oxidation based peptide labeling 23 and nucleic acid crosslinking methodologies 24 the current work again testifies to the usefulness and versatile application of a simple and small aromatic furan moiety for the decoration and conjugation of different biomacromolecules.…”