[Séminaires de l’UMR] Dr. Christelle Hureau, CNRS Toulouse

Sep 11, 2024

A shortjourney into the role of metal ions in Alzheimer’s disease.

Esmieu Charlène,aEmilie Mathieu,a Geneviève Pratviel and Christelle Hureau.a,*

Laboratoire de Chimie de Coordination, 205 Route deNarbonne, 31077 Toulouse cedex04, France

Alzheimer (AD) is a multifactorial pathologywhere two key events have been linked to the etiology of the disease: (i) theself-assembly process of the Alzheimer-related amyloid-β (Aβ) peptides leading to the deposits of Aβ amyloids inthe senile plaques detected in AD patients [1] and (ii) oxidativestress.[2]  Metal ions (mainly copper andzinc) have been found in the senile plaques in abnormally high level. They canmodulate the self-assembly of the Aβ peptides and Aβ-bound copper ions can catalyze the production of Reactive OxygenSpecies. They are thus key players in the pathology.

During the talk, I will give an overview of theapproaches we have developed in the last years to (i) first understand at themolecular level how metal ions are linked to the fate of the disease in connectionwith the modulation of Aβ self-assembly and with Aβ-bound Cu-induced ROS production [1-3] and to (ii) overcome theirdeleterious effects by new copper-targeting molecules,[3-5] or inorganicchaperons of the Aβ self-assembly.[5] 

1.            Atrian-Blasco, E.; Gonzalez, P.;Santoro, A.; Alies, B.; Faller, P.; Hureau, C., Cu and Zn coordination toamyloids: a chemistry of pathological importance ? Coord. Chem. Rev. 2018, 371, 38-55.

2.            Cheignon, C.; Tomas, M.;Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F., Oxidative stressand the amyloid beta peptide in Alzheimer’s Disease. Redox Biology 2018, 14, 450-464.

3.            Esmieu, C.; Guettas, D.;Conte-Daban, et al., Copper-Targeting Approaches in Alzheimer’s Disease: How ToImprove the Fallouts Obtained from in Vitro Studies. Inorg. Chem. 2019, 58, 13509-13527.

4.            M. Okafor, P. Gonzalez, P. Ronot, et al. Development of Cu(II)-specific peptideshuttles capable of preventing Cu–amyloid-β toxicity and importing bioavailable Cuinto cells. Chem. Sci. 2022, 13, 11829-40

5.            E.Atrian-Blasco, L. De Cremoux, X. Lin, R. Mitchell-Heggs, L. Sabater, S.Blanchard and C. Hureau. Keggin-typePolyoxometalates as Cu(II) chelators in the context of Alzheimer’s disease, Chem. Commun., 2022, 58, 2367-70. 

 

[Séminaires de l’UMR] Dr. Sébastien Vidal, ICSN Institut de chimie des substances naturelles, CNRS

Sep 11, 2024

Supramolecular Glycosciences and Applications.

Pseudomonas aeruginosa is apathogen responsible for numerous diseases, mostly found in hospitals as acause for nosocomial infections. While the bacterium is rather inoffensive forhealthy people, immuno-compromised patients are much more exposed to suchinfections, which can be lethal. Moreover, it is quite difficult to cure aninfection involving Pseudomonasaeruginosa due to its high resistance to antibiotics. Anti-adhesivestrategies are inhibiting the adhesion of bacteria to host cells. Two solublemultivalent lectins (LecA and LecB) have been identified in this process.

 

Wehave studied the multivalent effect and designed several multivalentglycoclusters to inhibit these lectins with applications in vivo towards potential therapeutic anti-infectious agents. Nonetheless,whilea typical medicinal chemistry approach goes through the syntheses andinhibition assays of individual inhibitor candidates, dynamic combinatorialchemistry provides a rapid access to an equilibrating mixture of inhibitorcandidates through reversible covalent bonds under thermodynamic control. Wehave designed dynamic combinatorial libraries (DCLs) of glycoclustersself-assembling through disulfide bonds which composition can be modified uponan external stimulus such as lectins.

We have also demonstrated the influence of a modellectin (ConA) and its amplification of tri- and four-member ring macrocyles. Weperformed the same study with LecA and LecB toward potential therapeuticapplications.