1) Cu and Zn in biological systems.

The general aim is to understand the role of Cu and Zn ions in the biological processes. Cu and Zn are mainly bound to peptides and proteins, where they perform essential biological functions. Cu and Zn serve mostly as catalytic centers and, often, Zn acts as structural elements or as messenger. Miss-regulation of Cu and Zn are often observed in disease and involve often Cu or Zn-binding to off-targets.

1.1) Cu and Zn binding to the peptide amyloid-beta linked to Alzheimer’s disease: This subtopic was one of the central theme during the last years. Amyloid plaques are a hallmark of Alzheimer’s disease patients and they consist mainly of the peptide amyloid-beta in form of fibrils due to the self-assembly of the peptide. High amounts of Cu, Zn and Fe were found in these plaques. Our group is interested in the characterization of the interaction of Cu and Zn with amyloid-beta, the impact on the self-assembly and in the case of Cu on the redox activity. Indeed Cu-amyloid-beta is redox competent and can produce reactive oxygen species, which might contribute to the oxidative stress observed in Alzheimer.

1.2) Cu- and-Zn-trafficking between proteins and other biomolecules, related to Alzheimer’s or other diseases: We are also interested in the Cu and Zn trafficking around amyloid-beta, i.e. to decipher which proteins can provide Cu or Zn to Abeta, and which could retrieve it. This is important because it is thought that Cu and Zn bound to amyloid-beta increase their toxicity. We investigate different metal-binding proteins/molecules like metallothionein, serum albumin, glutathione, cysteine etc. concerning Cu transfer from and off amyloid-beta. This should contribute to answer the question why Cu/Zn are bound to amyloid-beta in Alzheimer’s disease, but not under healthy conditions.

2) Synthesis of peptides or peptide-hybrides for application for antibiotics, imaging, as metal-sensor etc.

The team is also specialized in the field of peptide/protein synthesis allowing to obtain genetically encoded biomolecules such as peptides (<50 AA) or small folded proteins (<150 AA) by using Solid Phase Peptide Synthesis (SPPS Fmoc/tBu) and Chemical ligation (NCL, SEA ligation) technics. Also, the introduction of unnatural amino acids modified by organic dye fluorophores, biomolecules or biosensors give access to a large variety of metal binding peptides/proteins helping to develop applications in the field of :

2.1) Conception of metallo-peptides for different applications (for instance anti-microbial) Peptide bearing a N-terminus metal binding site (such as ATCUN motif) or an organic ligand (such as phenanthroline, bi-pyridine …) to chelate a metal ions (Copper, Nickel, Silver … to equip the peptide with a metal based activity (like ROS production, hydrolase, etc.).

2.2) The fact that peptides are involved in biological events (amyloid aggregation, metal transport, oxidative stress) makes them a suitable platform to develop sensors. Indeed, a simple idea is to graft a chromophore (or a FRET couple) onto a peptide, in a way that does not disturb the peptide’s role in the event. If the chromophore’s spectral properties are affected by the event, this molecule is then a good reporter of this biological event. Peptide-based sensors are particularly interesting for their biological relevance since they are almost identical to the natural molecules involved in the phenomenon seek to be monitored. Eventually, these probes would expand the toolbox for in vitro and/or in vivo monitoring and imaging, opening the door for a better understanding of biochemical events taking place in normal or pathological conditions.

3) Peptide self-assembly for biocatalysts or biomaterials.

Based on the expertise of the group in manipulating and characterizing amyloid peptides, we aim at designing non-natural peptides able to form fibers for biomaterials applications. As demonstrated by natural silks (from silkworm or spirders), protein-based material holds great potential in terms of mechanic properties. Plus, since they are bio-polymers, they can be ultimately produced from biological, renewable sources. First, the aim is to explore the link between the peptide sequence and the properties of the final material. This means that we seek at controlling (i) the peptide’s assembly, (ii) the folding of these peptides, and try to use it to tune the morphology and mechanical properties of the biomaterial. Second, onto these peptides, we aim at engineering metal sites, for structural purpose or to perform catalysis. Here, the challenge lies in controlling the properties of the metal site (coordination sphere, stability, catalytic activity).