Bioconjugation of oligonucleotides via the sulfo-click reaction

Département des Analogues et Constituants des Acides Nucléiques - Equipe ChemBioNAC
Institut Des Biomolécules Max Mousseron - UMR 5247 CNRS - UM - ENSCM
Pôle Chimie Balard Recherche, 1919 route de Mende, 34293 Montpellier cedex 5

Full offer available at :https://chembionac.com/opportunities/

Chemical modification of oligonucleotides is a corner stone in medical diagnostics, antisense therapies, and chemical biology. Among bioconjugation tools, the sulfo-click reaction between a sulfonyl azide and a thioacid yields a stable and biocompatible N-acylsulfonamide linkage without requiring toxic metal catalysts. Over the past decade, our group has deeply studied the sulfo-click reaction, successfully tailoring it for demanding applications in nucleic acid chemistry, bioconjugation, and medicinal chemistry.^1-5

However, direct incorporation of sulfonyl azides onto oligonucleotides during automated solid-phase synthesis is heavily hampered by their high reactivity toward phosphorus(III) species (Staudinger-type side reactions) and their instability under the basic conditions required for nucleobase deprotection. To circumvent these limitations, our team has recently developed an innovative strategy involving the post-synthetic introduction of the sulfonyl azide onto the oligonucleotide. The objective of this project is to build upon these promising first results to fully expand and optimize this post-synthetic methodology. Following the synthesis of the novel phosphoramidite synthon, the student will synthesize modified DNA/RNA sequences and optimize the post-synthetic functionalization of these oligonucleotides with the sulfonyl azide moiety. Finally, the newly generated sulfonyl azide oligonucleotides will be engaged in orthogonal sulfo-click bioconjugations using various functional thioacids.

Our team has a long standing interest in the design and synthesis of natural or modified oligonucleotides for diagnostic, sensing and therapeutic purposes^{6, 7} and is equipped with several DNA and RNA synthesizers as well as the required analytical equipment (HPLC, MALDI-TOF, flash purification devices, etc…).

References:

1. G. Clavé, E. Dursun, J. J. Vasseur and M. Smietana, Org. Lett., 2020, 22, 1914-1918 ; 2. R. Amador, A. Delpal, B. Canard, J. J. Vasseur, E. Decroly, F. Debart, G. Clavé and M. Smietana, Org. Biomol. Chem., 2022, 20, 7582-7586 ; 3. R. Amador, A. Tahrioui, M. Barreau, O. Lesouhaitier, M. Smietana and G. Clavé, RSC Med. Chem., 2023, 14, 1567-1571 ; 4. R. Amador, J. J. Vasseur, G. Birkus, E. Bignon, A. Monari, G. Clave and M. Smietana, Org. Lett., 2024, 26, 819-823 ; 5. R. Amador, C. Baraguey, G. Clavé and M. Smietana, Org. Biomol. Chem., 2025, 23, 9576-9581 ; 6. G. Clavé, M. Reverte, J.-J. Vasseur and M. Smietana, RSC Chem. Biol., 2021, 2, 94-150 ; 7. M. Debiais, J. J. Vasseur and M. Smietana, Chem. Rec., 2022, 22, e202200085.

The candidate will ideally possess a strong background in organic synthesis and an interest in nucleic acids chemistry and modern bioconjugation techniques. Notably, funding is available for a PhD position, offering the opportunity to continue as a PhD student in our team.