Water-Soluble Isocyanides for Passerini-Mediated Peptide Modification and Ligation
- 1Biobased Organic Chemistry, Maastricht University, Urmonderbaan 22, Geleen, Netherlands, 6167RD
- 2EnzyTag B.V., Daelderweg 9, Nuth, Netherlands, 6361HK
Abstract
Protein solubility is a key factor of peptide and protein modification and downstream application, yet chemical functionalization under aqueous conditions often compromise solubility. Here, we introduce a new class of ionic, water-soluble isocyanides for the functionalization of peptide carboxyl groups under aqueous conditions. By combining strong hydrogen-bonding motifs with ionic functionalities, these reagents provide enhanced water solubility while enabling modulation of peptide isoelectric points. The isocyanides were synthesized via a concise route and applied successfully in Passerini multicomponent reactions without observable precipitation. The resulting esterified peptides remained water-soluble even for highly hydrophobic sequences. They also served as competent substrates for omniligase-1-mediated ligation, with polar cationic modifications showing particularly favorable performance. These results demonstrate that rational isocyanide design can overcome solubility losses associated with peptide esterification, expand the scope of isocyanide-based ligation chemistry in aqueous environments, and provide a platform for tuning protein surface charge.
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BibTeX
@misc{lambers2026watersoluble,
title = {{Water-Soluble Isocyanides for Passerini-Mediated Peptide Modification and Ligation}},
author = {M. Lambers and J. Hanssens and T.A.A. Combaret and G. Bartkiewicz and L. J. van den Bos and J. M. Saya},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010005/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010005/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Water-Soluble Isocyanides for Passerini-Mediated Peptide Modification and Ligation
AU - M. Lambers
AU - J. Hanssens
AU - T.A.A. Combaret
AU - G. Bartkiewicz
AU - L. J. van den Bos
AU - J. M. Saya
PY - 2026
DA - 2026/10/06
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010005/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010005/v1
AB - Protein solubility is a key factor of peptide and protein modification and downstream application, yet chemical functionalization under aqueous conditions often compromise solubility. Here, we introduce a new class of ionic, water-soluble isocyanides for the functionalization of peptide carboxyl groups under aqueous conditions. By combining strong hydrogen-bonding motifs with ionic functionalities, these reagents provide enhanced water solubility while enabling modulation of peptide isoelectric points. The isocyanides were synthesized via a concise route and applied successfully in Passerini multicomponent reactions without observable precipitation. The resulting esterified peptides remained water-soluble even for highly hydrophobic sequences. They also served as competent substrates for omniligase-1-mediated ligation, with polar cationic modifications showing particularly favorable performance. These results demonstrate that rational isocyanide design can overcome solubility losses associated with peptide esterification, expand the scope of isocyanide-based ligation chemistry in aqueous environments, and provide a platform for tuning protein surface charge.
ER -