Mark D. Nolan – report on the stay on a scientific internship under the EPS Mobility Fellowship

I am a final year PhD candidate in the group of Prof. Eoin Scanlan in Trinity College Dublin, and my research thus far has focused on using the photochemical thiol-ene reaction for peptide modification,1 including for macrocyclisation2 and green bioconjugation.3

Thanks to the EPS Mobility Fellowship, I was able to spend September to December 2022 at the Swiss Federal Institute of Technology Lausanne (EPFL) in the lab of Prof. Christian Heinis. Current research in this lab focuses on development of new therapeutics through high-throughput peptide macrocycle synthesis. This has led to development of new methodology for generation of high-purity compounds without chromatographic purification. The aim of the project to be performed during this placement was to develop a photochemical Thiol-Ene “Click” based methodology to allow late-stage diversification of alkene-containing peptide macrocycles that would give high purity crude mixtures.

In high-throughput chemistry, the need for chromatographic purification can significantly extend the time required for preparation of a library of compounds. Recent work in the Heinis lab has shown that optimised and novel techniques can afford large numbers of compounds that can be screened without such purification. Thiol-Ene “Click” has shown significant promise in peptide and protein chemistry for chemoselective modification, and the characteristically high yields and low side products associated with this reaction lend it well to the aim of accessing high purity crude mixtures. During this research placement, we developed methodology for high-throughput modification of peptidic macrocycles that gives high quality crude mixtures. I have since returned to Trinity College Dublin to use the chemistry developed while at EPFL to obtain improved affinity binders for biological targets relevant to my research.

As well as being able to perform this research thanks to the expertise of the members of the Heinis lab and using the high-throughput instrumentation available, this secondment gave me the opportunity to attend great talks as part of their chemical biology seminar series, as well as the ability to explore Switzerland. I am extremely grateful to the European Peptide Society for their financial support for this secondment, as well as to my host lab at EPFL, in particular Dr. Alexander Lund Nielsen and Prof. Christian Heinis.

Members of the Heinis group at a traditional Swiss Christmas market.

References:

(1) Nolan, M. D.; Scanlan, E. M. Applications of Thiol-Ene Chemistry for Peptide Science. Frontiers in Chemistry. Frontiers November 12, 2020, p 583272. https://doi.org/10.3389/fchem.2020.583272.

(2) Nolan, M. D.; Shine, C.; Scanlan, E. M.; Petracca, R. Thioether Analogues of the Pituitary Neuropeptide Oxytocin via Thiol–Ene Macrocyclisation of Unprotected Peptides. Org. Biomol. Chem. 2022, 20 (42), 8192–8196. https://doi.org/10.1039/D2OB01688E.

(3) Nolan, M. D.; Mezzetta, A.; Guazzelli, L.; Scanlan, E. M. Radical-Mediated Thiol-Ene ‘Click’ Reactions in Deep Eutectic Solvents for Bioconjugation. Green Chem. 2022, 24 (4), 1456–1462. https://doi.org/10.1039/d1gc03714e.