11/11/2025
Breaking barriers in bioconjugation chemistry with aromatic carbocations
A team led by Prof. Marcos Garcia Suero at the Institute of Chemical Research of Catalonia (ICIQ) has found a way to overcome a long-standing limitation: performing a carbocation reaction in peptides and proteins in aqueous media. The study marks a milestone in the field of for site-selective peptide and protein bioconjugation.
First author Dr. Adriana Faraone reflected on the journey: "What we achieved was to learn how to work with these biomolecules which require different chemical understanding and technical expertise, and we merged organic chemistry with the field of bioconjugation with great results."
The team's approach relies on cyclopropenium cations (CPCs), small aromatic carbocations capable of selectively reacting with cysteine residues. This site-selective modification enables the direct installation of tetrasubstituted cyclopropenes, which can serve as a "chemical handle" for further transformations, avoiding the use of metals or hazardous reagents typically involved in similar processes.
Co-first author Matteo Balletti explained, "Our strategy is a new bioconjugation method able to directly insert cyclopropene motifs in complex biomolecules. This could have an impact on the implementation of new bioconjugates-which are synthetically modified peptides or proteins-that can aid the development of peptidomimetic drugs."
Bioconjugation plays a crucial role in the development of modern therapeutics such as antibody-drug conjugates (ADCs), PEGylated proteins and peptidomimetics. These synthetically modified biomolecules combine the precision of biological systems with the versatility of chemistry, helping researchers design more selective and effective treatments. Discovering new and simpler ways to attach chemical groups to proteins is therefore a key challenge for pharmaceutical and biotechnology research.
According to Prof. Suero, "This discovery extends our cyclopropenium chemistry beyond small molecules, into the realm of biomacromolecule functionalization in physiological media." At the start of the project, the team faced significant challenges. Cyclopropenium cations (CPCs) are highly reactive towards water, making their use in aqueous bioconjugation particularly difficult. Initial trials in organic solvents showed promise, but transferring the reaction to biologically relevant conditions required extensive optimisation.
The project also lacked previous in-house expertise in peptide and protein chemistry. Dr Adriana Faraone joined the group after completing her PhD with Prof. Paolo Melchiorre and successfully developed the methodology that enabled CPC-based bioconjugation in water. Dr Matteo Balletti later expanded the study, refining the approach and identifying a complementary thiol-ene bioorthogonal process.
The ICIQ-SO Strategic Funding awarded have enabled the advancement of this project. Launched in 2021 as part of the Severo Ochoa research plan, this initiative supports one-year, high-risk/high-gain research projects (not related to previous research done) to a Group Leader that align with ICIQ's strategic priorities. This project have received funding from the Spanish State Research Agency / Ministry of Science, Innovation and Universities through the "Severo Ochoa" Centres of Excellence Programme (CEX2019-000925-S, MICIU/AEI/10.13039/501100011033) as well as from AEI (PID2022-140286NB-I00), ERC (865554) and MSCA (101032589)
Source: Institute Catalan