Macrocyclic peptides have been identified as key backbones in several biologically active compounds. They have been considered as great inspiration in the development of novel cyclic scaffolds in medicinal chemistry, notably in the introduction of α-helically constricted stapled peptides with the ability to mimic biologically relevant α-helices. DNA-binding transcription factors often bind their DNA promoter through an α-helix, making a parallel with stapled peptides as inhibitors. Despite this relevant feature, DNA-binding stapled peptides are highly unrepresented in the literature, as will be discussed here in a review. We also further expand this area of research with a study of DNA binding stapled peptide ana-logues with the goal of optimizing and investigating the DNA binding and antivirulence of an RpoN-based stapled peptide. Cyclic depsipeptides are highly biologically active natural product molecules however their synthesis can be challenging with the presence of a macrolactone. Due to this complexity, solid phase peptide synthesis strategies have been utilized to access peptide intermediates that can be synthetically macrocyclized using solution phase or on-resin approaches via macrolactam or macrolactone formation. A representative number of total syntheses in the literature is reviewed. Furthermore, we describe here the chemical total synthesis and chemoenzymatic synthesis of seongsanamide E cyclic depesipeptide via thioesterase medi-ated macrolactonization. Cyclic depsipeptides also play major roles in their producing organisms, notably siderophores capable of chelating and transporting iron. The biosynthesis of fungal siderophores is poorly explored, such as the iterative mechanism of oligomeric compound fusarinine C. We explore the synthesis of the previously never synthesized fusarinine C monomer to be utilized as a di-domain inhibitor of the adenylating-thiolation domains of the non-ribosomal peptide synthetase (NRPS) SidD.

Les glycosidases sont des enzymes impliquées dans de nombreux processus biologiques. Entre autres, elles sont responsables de la dégradation des déchets polysaccharidiques de nos cellules. Lorsqu’une modification génétique touche un gène qui code pour une de ces enzymes, des pathologies graves regroupées sous l’appellation de « maladies lysosomales » peuvent être déclenchées. L'objectif de ce projet a été de proposer une méthode de synthèse efficace de molécules potentiellement actives spécifiquement sur l'une ou l'autre de ces maladies. Les molécules ciblées sont des inhibiteurs de glycosidases de la famille des aminocyclitols, utilisés dans une stratégie thérapeutique émergente « par molécules chaperonnes ». La méthode de synthèse développée s’appuie sur une étape enzymatique clé utilisant les aldolases comme catalyseurs et répondant aux contraintes environnementales actuelles de la chimie verte. Nous avons atteint nos objectifs grâce à l’utilisation de trois aldolases différentes, produites et purifiées pour la première fois au sein de notre laboratoire. Il s’agit de la fuculose-1-phosphate aldolase F1PA, de la rhamnulose-1-phosphate aldolase R1PA et de la nouvellement découverte fructose-6-phosphate aldolase FSA. La formation d’une quarantaine de nitrocyclitols, de stéréochimies définies, précurseurs des aminocyclitols correspondant, a ainsi été réalisée avec de très bons rendements de synthèse. / Glycosidases are enzymes involved in many biological processes. For example, they are responsible for breaking up polysaccharide waste materials of our cells. When a genetic mutation concerns a gene encoding for one of theses enzymes, acute pathologies named lysosomal storage disorders can appear. Aim of this work was to find an effective synthesis method of molecules potentially active specifically on one or others diseases. Target molecules are glycosidases inhibitors from the aminocyclitols family, used in an emergent strategy “by molecular chaperones”. The method of synthesis developed in the course of this work is based on an enzymatic key step using aldolases as catalyst, and follows current environment constraints of the green chemistry concept. Goals were reached thanks to the use of three different aldolases, produced and purified for the first time in our lab. It consists in fuculose-1-phosphate aldolase F1PA, rhamnulose-1-phosphate aldolase R1PA and the newly discovered fructose-6-phosphate aldolase FSA. Formation of around forty nitrocyclitols (aminocyclitols precursors) with a defined stereochemistry was realised with very good yields of synthesis.