Mathieu Fossepre

One-Pot Self-Assembly of Peptide-Based Cage-Type Nanostructures using Orthogonal Ligations

The designed arrangement of biomolecular entities within monodisperse nanostructures is an important challenge toward functional biomaterials. We report herein a method for the formation of water-soluble peptide-based cages using orthogonal ligation reactions-acylhydrazone condensation and thiol-maleimide addition. The results show that using preorganized cyclic peptides and heterobifunctional spacers as building blocks and a set of orthogonal and chemoselective ligation reactions enable cage formation in one pot from six components and through eight reactions. Molecular modelling simulations reveal the structural dynamics of these structures. Finally, we exploited the reactional dynamics of the acylhydrazone by demonstrating the controlled dissociation of the cage through directed component exchange.

Photomodulation of DNA-templated supramolecular assemblies

A new type of DNA ligand that contains a phosphate-binding group and a photoresponsive azobenzene moiety is reported. When the azobenzene is in trans configuration, the ligand binds to the minor groove of a double-stranded DNA, whereas it partially desorbs upon trans-cis isomerisation with light. The ability to photoswitch the ligand upon interaction with DNA is evidenced by (chir)optical signatures, and deciphered by the differences of binding geometry, stability, and dynamics of the DNA/ligand complexes for the two isomers. We exploit these properties to photomodulate DNA-templated self-assembly, through the incorporation of another π-stacking DNA ligand, which together with the photoresponsive ligand form mixed supramolecular complexes along DNA. Our study demonstrates that well-designed photoresponsive DNA binders can be used to modulate multicomponent supramolecular DNA assemblies.

Toward a new and noninvasive diagnostic method of papillary thyroid cancer by using peptide vectorized contrast agents targeted to galectin-1

The incidence of papillary thyroid cancer has increased these last decades due to a better detection. High prevalence of nodules combined with the low incidence of thyroid cancers constitutes an important diagnostic challenge. We propose to develop an alternative diagnostic method to reduce the number of useless and painful thyroidectomies using a vectorized contrast agent for magnetic resonance imaging. Galectin-1 (gal-1), a protein overexpressed in well-differentiated thyroid cancer, has been targeted with a randomized linear 12-mer peptide library using the phage display technique. Selected peptides have been conjugated to ultrasmall superparamagnetic particles of iron oxide (USPIO). Peptides and their corresponding contrast agents have been tested in vitro for their specific binding and toxicity. Two peptides (P1 and P7) were selected according to their affinity toward gal-1. Their binding has been revealed by immunohistochemistry on human thyroid cancer biopsies, and they were co-localized with gal-1 by immunofluorescence on TPC-1 cell line. Both peptides induce a decrease in TPC-1 cells’ adhesion to gal-1 immobilized on culture plates. After coupling to USPIO, the peptides preserved their affinity toward gal-1. Their specific binding has been corroborated by co-localization with gal-1 expressed by TPC-1 cells and by their ability to compete with anti-gal-1 antibody. The peptides and their USPIO derivatives produce no toxicity in HepaRG cells as determined by MTT assay. The vectorized contrast agents are potential imaging probes for thyroid cancer diagnosis. Moreover, the two gal-1-targeted peptides prevent cancer cell adhesion by interacting with the carbohydrate-recognition domain of gal-1.

Self-assembly and chiroptical properties in supramolecular complexes of adenosine phosphates and guanidinium-bispyrene

Supramolecular systems that respond to the hydrolysis of adenosine phosphates (APs) are attractive for biosensing and to fabricate bioinspired self-assembled materials. Here, we report on the formation of supramolecular complexes between an achiral guanidinium derivative bearing two pyrene moieties, with each of the three adenosine phosphates: AMP, ADP, and ATP. By combining results from circular dichroism spectroscopy and molecular modeling simulations, we explore the induced chirality, the dynamics of the complexes, and the interactions at play, which altogether provide insights into the supramolecular self-assembly between APs and the guanidinium-bispyrene. Finally, we identify the chiroptical signals of interest in mixtures of the guanidinium derivative with the three APs in different proportions. This study constitutes a basis to evolve toward a chiroptical detection of the hydrolysis of APs based on organic supramolecular probes.