In 1996, scientists discovered a connection between the gene for the human protein frataxin (FXN) and the neurodegenerative disease Friedreich’s ataxia (FRDA). Decreased FXN levels result in a variety of aberrant phenotypes including loss of activity for iron-sulfur containing enzymes, mitochondrial iron accumulation, and susceptibility to oxidative stress. These symptoms are the primary focus of current therapeutic efforts. In contrast our group is pursuing an alternate strategy of first defining FXN function at a molecular level then using this information to identify small molecule functional replacements. Recently, our group has discovered that FXN functions as an allosteric activator for the human Fe-S cluster assembly complex. The work presented here helps to further define molecular details of FXN activation and explain how FRDA missense mutants are functionally compromised. First, the FRDA missense mutants L182H and L182F were investigated. Unlike other characterized FRDA missense mutants, the L182F variant was not compromised in its ability to bind and activate the Fe-S assembly complex. The L182H variant exhibited an altered circular dichroism signature; suggesting a change in secondary structure relative to native FXN, and rapidly degraded. Together these studies suggest that L182 variants are less stable than native FXN and are likely prone to degradation in FRDA patients. Second, as a regulatory role of FXN suggests that its function is likely controlled by environmental stimuli, different maturation forms of FXN as well as post-translational modification mimics were tested as mechanisms to control FXN regulation. Here experiments were designed to test if a larger polypeptide form of FXN represents a functional form of the protein. Kinetic and analytical ultracentrifugation studies revealed a complex heterogeneous mixture of species some of which can activate the Fe-S assembly complex. A previously identified acetylation site was also tested using mutants that mimic acetylation. These mutants had little effect on the ability of FXN to bind and activate the assembly complex. Third, mutagenesis experiments were designed in which the FXN surface residues were replaced with alanine and the resulting variants were tested in binding and activity assays. These experiments revealed a localized “hot-spot” on the surface of FXN that suggests small cyclic peptide mimics might be able to replace FXN and function as FRDA therapeutics. Unexpectedly, one of the FXN variants exhibited significantly tighter binding and could have relevance for therapeutic development.

Ephrin type-B receptor 2 (EphB2) is a receptor tyrosine kinase which phosphorylates proteins and thereby regulates cell migration, vascular development, axon guidance synaptic plasticity, and formation of borders between tissues. It has been seen overexpressed in several cancers, which make it an interesting protein to study. In this thesis EphB2 kinase domain (KD) and juxtamembrane segment with kinase domain (JMS-KD) have been expressed, purified and studied using analytical ultracentrifugation to evaluate the oligomerisation of the KD and how the double mutation S677/680A affects this. A program for data analysis have been written and used for analysis of the acquired data. The values of the dissociation constant were 2.94±1.04 mM for KD wild type and 3.46±2.26 mM for JMS-KD wild type have been calculated. Due to varied problems with the measurements no data was acquired on the double mutant, and not enough data was gained to draw any conclusions. Additional experiments will be needed to understand the oligomerisation of this intriguing protein.

As one of the mechanisms of antibiotic resistance, bacteria use several families of membrane-embedded α-helical transporters to remove cytotoxic molecules from the cell. The small multidrug resistance protein family (SMR) is one such group of drug transporters that because of their relative small size [ca. 110 residues with four transmembrane (TM) helices] must form at the minimum dimers to efflux drugs. We have used the SMR homologue Hsmr from Halobacterium salinarum to investigate the oligomerization properties of the protein family at TM helix 4. We produced point mutations along the length of the TM4 helix in the full length Hsmr protein and assayed their dimerization and functional properties via SDS-PAGE and bacterial cell growth assays. We found that Hsmr forms functionally dependent dimers via an evolutionarily conserved 90GLxLIxxGV98 small residue heptad repeat. Upon investigation of the large hydrophobic residues in this motif by substituting each large residue to Ile, Leu, Met, Phe, and Val, we determined that Hsmr efflux function relies on an optimal level of dimerization. While some substitutions led to either decreased or increased dimer and substrate-binding strength, several Ile94 and Val98 mutants were equal to wild type dimerization levels but were nonfunctional, leading to the hypothesis of a mechanistic role at TM4 in addition to the locus of dimerization. The functionally sensitive TM4 dimer represents a potential target for SMR inhibition using a synthetic TM4 peptide mimetic. Using exponential decay measurements from a real-time cellular efflux assay, we observed the efflux decay constant was decreased by up to ~60% after treatment with the TM4 peptide inhibitor compared to control peptide treatments. Our results suggest that this approach could conceivably be used to design hydrophobic peptides for disruption of key TM-TM interactions of membrane proteins, and represent a valuable route to the discovery of new therapeutics.

The human retinoid X receptor alpha (hRXRalpha) is a member of the nuclear receptor super-family of ligand-activated transcription factors. The Doyle laboratory has previously engineered a variety of functional hRXRalpha variants that activate gene expression in response to synthetic ligands (LG335 and γ-oxo-1-pyrenebutyric acid), compounds that are poor activators of wild-type hRXRalpha. The variants generally no longer respond to the wild-type ligand 9-cis retinoic acid. To enable targeting of these engineered receptors to arbitrary DNA sequences, we developed a program, ESPSearch, for identifying short or specific sequences in DNA or protein. ESPSearch enables identification of combinations of known zinc finger motifs to target arbitrary genes, as well having several other applications. The ability to target any DNA sequence means that the engineered receptors can be directed to control any gene. The ligand binding, self-association, coactivator interactions, and unfolding properties of the ligand binding domain of wild-type hRXRalpha were characterized. Our expression and purification protocol improves upon existing methods, providing high purity protein in a single step with more than twice prior yields. A general fluorescence-based method for measuring ligand affinity with hRXRalpha was developed, and used to determine binding constants for the small molecules. The presence of a peptide containing the binding motif from coactivator proteins (LxxLL) differentially increased the affinity of the receptor for the ligands. Assays to determine the self-association give a Kd for the dimer-tetramer equilibrium of 35 µM. hRXRalpha was found to denature irreversibly when heated, but shifts in apparent Tm due to ligands correlates strongly with the ligand binding affinities. Our results clarify disparities in existing reports and provide a benchmark for comparison. Reliable analysis of our data led to the development of a computer program for rigorous, automated data fitting. Nine functional variants of hRXRalpha were characterized to probe correlations between biophysical properties and the observed functional activity of the receptors, which differ significantly from wild-type. Although the correlation between ligand binding affinity and melting temperature was strong for all variants, there was essentially no correlation between ligand binding and activation of the variants. The mutations, which are all contained within the binding pocket, have significant long-range effects on the protein, causing changes in ligand-LxxLL interactions and oligomerization of the variants. Experimental and computational analysis of selected mutations suggests that they are highly coupled, complicating protein design. However, the large variation in properties amongst the variants also suggests that hRXRalpha can be mutated extensively while still retaining function. The long-range impact of binding pocket mutations will need to be taken into account in future engineering projects, as hRXRalpha is a flexible, dynamic protein.

L’objectif de cette thèse portait sur la synthèse de complexes portant un ligand NHC associé à une fonction oxygénée et à leur application en catalyse d’oligomérisation de l’éthylène. Dans le but de synthétiser des complexes avec des ligands NHCalcool, les complexes d’argent correspondants ont été synthétisés et utilisés en transmétallation. Aucun résultat concluant n’a pu être obtenu avec le nickel à cause de l’acidité du proton alcoolique. Mais un ligand NHC-alcoolate a pu être obtenu par déprotonation directe du pro-ligand avec une base forte. Il fut alors possible d’accéder à des complexes de nickel polynucléaires, certains incorporant dans leur structure des cations lithium provenant de la base utilisée. Par comparaison, des complexes de palladium ont été synthétisés avec des NHCs-alcool ou -alcoolate par réaction des pro-ligands avec Pd(acac)2 suivie de réactions acido-basiques. Etant donné la difficulté d’obtention des complexes de nickel avec des ligands NHC-alcool, la fonction éther a été étudiée. Les complexes résultants ont été testés en oligomérisation de l’éthylène. / The purpose of this work was the synthesis of complexes bearing O-functionalized NHC ligands in order to test their catalytic properties in ethylene oligomerization. In order to have access to alcohol-functionalized complexes, the corresponding silver complexes were synthesized for transmetallation purpose. Whereas no concluding results were obtained with the alcohol function in association with nickel, it was possible to access an alcoholate-functionalized NHC ligand by deprotonation of the corresponding pro-ligand. Thus, polynuclear nickel complexes were prepared, some of them included in their structure a lithium cation originating from the base. For comparison, alcohol- and alcoholate-functionalized NHC palladium complexes were synthesized by direct reaction of the pro-ligand with Pd(acac)2 followed by acidobasic reactions. Because of the complexity of the chemistry of NHC-alcohol ligands associated with nickel, the ether functionality was explored. A library of nickel complexes was synthesized and tested in the catalytic ethylene oligomerization.

L'éthylène représente l'une des molécules plateforme les plus importantes de l'industrie de la chimie avec une capacité de production de l'ordre de 140 millions de tonnes par an. La recherche réalisée dans cette thèse porte sur le développement de nouveaux catalyseurs hétérogènes, ainsi que des procédés pour l'oligomérisation et la métathèse de l'éthylène. Les catalyseurs sont des matériaux mésoporeux (topologie SBA-15 ou SiO2 commerciale) au Ni (pour l'oligomérisation) et au Mo (pour la métathèse). Les catalyseurs Ni-AlSBA-15 (~ 2,6% Ni, Si/Al ~ 7) ont été préparés par alumination post-synthèse de la silice SBA-15 avec de l'aluminate de sodium, suivie d'un échange d'ions avec du nickel. D'une manière similaire ont été préparés les catalyseurs Ni-AlSiO2. Les techniques de caractérisation, telles que diffraction des rayons X, sorption d'azote, MET, RMN de 27Al et 29Si ont prouvé le système de pores parfaite des solides SBA-15, avec de l'aluminium coordonnée principalement en mode tétraédrique dans le réseau de silice. Ni-AlSBA-15 et Ni-AlSiO2 présentent des comportements catalytiques exceptionnels dans la réaction d'oligomérisation de l'éthylène. A 150 ° C et 3,5 MPa, à la fois en mode discontinu et en flux, les catalyseurs sont très actifs (jusqu'à 175 g d'oligomères par gramme de catalyseur et par heure), sélectifs (oléfines en C4, C6, C8 et C10, aucun des produits de craquage) et stable (taux de conversion élevé pendant 80 h de réaction). Ces performances sont supérieures à celles présentées par d'autres catalyseurs hétérogènes à base de Ni, sans utiliser cocatalyseurs alkylaluminium. Un mécanisme impliquant des ntermédiaires metallocycliques est soutenu par nos résultats expérimentaux. Nous avons aussi développé un procédé original pour convertir directement l'éthylène en propylène, à travers des réactions en cascade, d'oligomérisation, d'isomérisation et de métathèse, avec deux catalyseurs hétérogènes solides très actifs. Dans un seul réacteur à flux et dans des conditions identiques, l'éthylène a été dimérisé/isomérisé sélectivement sur Ni-AlSBA-15 pour former le 2-butène, qui réagit avec l'excès d'éthylène dans une deuxième étape, sur un catalyseur au MoO3 pour produire du propylène. A 80 ° C et 3 MPa, des activités spécifiques allant jusqu'à 48 mmoles de propylene par gramme de catalyseur et par heure ont été obtenues. La désactivation et la régénération des catalyseurs ont été étudiées. Un mécanisme, en trois étapes (dimérisation/isomérisation/métahèse), sur trois sites différents (Ni+, H+ et respectivement Mo6+) a été proposé. MOTS CLES : éthylène ; propylène ; oligomérisation ; métathèse ; catalyse hétérogène ; Ni-AlSBA-15 ; MoO3 / Ethylene is one of the most important platform molecules of the chemical industry with a production capacity of around 140 million tons per year. The research conducted in this thesis focuses on the development of new heterogeneous catalysts and processes for the oligomerization and metathesis of ethylene. The catalysts are mesoporous materials (SBA-15 topology or commercial SiO2) with Ni (for the oligomerization) and with Mo (for metathesis). Ni-AlSBA-15 oligomerization catalysts (2.6 wt% Ni, Si/Al = 7) were prepared by post-synthesis alumination of SBA-15 silica with sodium aluminate, followed by ion exchange with nickel. In a similar manner was prepared the catalyst Ni-AlSiO2. Characterization techniques, including powder X-ray diffraction, N2 sorption, TEM, 27Al and 29Si MAS NMR proved the perfect pore system of the SBA-15 materials, with aluminum tetrahedrally mainly coordinated in the silica framework. Ni-AlSBA-15 and Ni-AlSiO2 exhibited outstanding catalytic behaviour in the oligomerization reaction of ethylene. At 150 °C and 3.5 MPa, in both batch and flow mode, the catalyst was highly active (up to 175 g of oligomers per gram of catalyst per hour), selective (C4, C6, C8, and C10 olefins, no cracking products) and stable (high conversion during 80 h on-stream). These performances were superior than those exhibited by other Ni-based heterogeneous catalysts, without using alkylaluminum cocatalysts. A mechanistic pathway involving metallacyclic intermediates is supported by the experimental results. Additionally, an original process for converting ethylene to propylene, involving cascade oligomerization/isomerisation/metathesis reactions, over two robust and highly active heterogeneous catalysts has been proposed. In a single flow reactor and under identical conditions, ethylene was first selectively dimerized/isomérized over Ni-AlSBA-15 catalyst to form 2-butene, which reacted then with the excess of ethylene over MoO3–based catalyst, to produce propylene. At 80°C and 3 MPa, specific activities up to 48 mmol of propylene per gram of catalyst per hour were obtained.KEYWORDS : ethylene ; propylene ; oligomerization ; metathesis ; heterogeneous catalysis ; Ni-AlSBA-15; MoO3

Os receptores tireoidianos (TRs) são proteínas envolvidas em várias funções fisiológicas importantes para os organismos, pois são potentes reguladores do desenvolvimento, divisão e diferenciação celular, metabolismo e homeostase. Eles são responsáveis pela regulação da transcrição de genes-alvo específicos, mediando efeitos pleiotrópicos de hormônios lipofílicos nas células. Na ausência de ligantes essas proteínas estão complexadas a correpressores, impedindo a transcrição de genes por elas regulados. Por outro lado, a presença do ligante induz à transcrição através da ligação a elementos responsivos do DNA e coativadores. Nesse trabalho alguns aspectos do TR foram evidenciados, permintindo-se um melhor conhecimento acerca do funcionamento e estrutura desse receptor. Os experimentos de oligomerização revelaram a presença dos tetrâmeros do TR, os quais estavam restritos ao Receptor X Retinóico, sugerindo mecanismos novos na regulação do receptor. Os ensaios de raios-X a baixos ângulos resultaram nos primeiros modelos estruturais de baixa resolução de construções maiores do TR, demonstrando o correto posicionamento de seus domínios em sua estrutura geral, o que forneceu informações importantes sobre sua estrutura geral. Os experimentos de fluorescência avaliaram a ligação desses receptores a diversos elementos responsivos, em termos de constantes de dissociação e seletividade para cada um deles. E, por fim, os experimentos de troca de hidrogênio por deutério revelaram a movimentação que ocorre no domínio de ligação do ligante do receptor antes e após a adição do ligante T3. Esses resultados ampliam um pouco mais os conhecimentos sobre os mecanismos de ação e sobre a estrutura quaternária dos TR, promovendo um melhor entendimento dos conceitos básicos envolvidos na atuação dessas macromoléculas, as quais estão inseridas em redes complexas de regulação e interação com outras proteínas. / The thyroid receptors (TRs) are proteins, which are involved in diverse and important physiological functions in the organisms, since they are regulators of development, cell divison and differentiation, metabolism and homeostasis. They are responsible by the regulation of specific gene transcription, through pleiotropic effects of lipophilic hormones in the cells. In the absence of the ligand these proteins are complexed to correpressors and block the transcription of genes that are regulated by them On the other hand, in the presence of the ligand transcription is induced through the binding of the receptors to DNA response elements and coactivators. New findings about TR described in this study helped to improve the understanding of the function and structure of the receptor. This was accomplished by: oligomerization experiments which showed the presence of TR tetramers, a quarternary structure described before only for the Retinoid Receptor X, and suggested new regulation mechanisms for the receptors; the small angle X-ray scattering assays which resulted in the first low resolution structural models of bigger constructions of TR, showing the correct position of TR domains and providing important information about the global TR structure; the anisotropy fluorescence experiments which evaluated the binding of these receptors to diverse response elements, in terms of dissociation constants and selectivity for each one of the HREs tested; and finally, the hydrogen/deuterium experiments which revealed the ligand binding domain mobility before and after the ligand addition. In summary, we can say that these results all together extended the knowledge about the TR action mechanisms and its quarternary strucuture, providing better understanding of the basic concepts involved in these macromolecules behavior, which are inserted into a complex network of regulation and interaction with other proteins.

A Esclerose Lateral Amiotrófica (ELA) é uma doença progressiva e fatal causada pela degeneração seletiva dos neurônios motores do cérebro e medula. Dos casos familiares de ELA (fELA), 20% são causados por mutações pontuais no gene da sod1. O ácido docosahexaenoico (C22:6, n-3, DHA) é um ácido graxo altamente insaturado, sendo um dos principais ácidos graxos da massa cinzenta do cérebro. Estudos têm correlacionado mutações de SOD1 com a formação de agregados que poderiam ser induzidos por ácidos graxos insaturados. O objetivo deste estudo foi avaliar os efeitos e mecanismos do DHA e de seus hidroperóxidos (DHAOOH) na agregação de SOD1 in vitro. As análises de dicroísmo circular (CD) mostraram mudanças na estrutura secundária de ambas as proteínas apo-SOD1WT e G93A promovidas pelo DHA, resultando em aumento de superfície hidrofóbica e formação de estruturas do tipo beta-amilóide, como mostrado pelos ensaios do bis- ANS e Tioflavina, respectivamente. Estas mudanças resultam na formação de agregados amorfos como observado por microscopia eletrônica de varredura (MEV). Espécies de alto peso molecular foram observadas nas incubações do DHA com as formas apo da SOD1 por SDS-PAGE sob condições não redutoras e também por cromatografia de exclusão por tamanho. A formação dos agregados mostrou-se dependente de resíduos de Cys na sua forma desprotonada, visto que agregados não foram observados na presença de beta-mercaptoetanol e sua formação foi inibida na presença de bloqueador de tióis e em pH ácido. Além disso, análises por cromatografia de exclusão mostraram que a agregação é dependente da insaturação e conformação cis dos ácidos graxos. Comparativamente ao DHA, os hidroperóxidos do DHA tiveram um efeito menor na agregação de SOD1, porém revelaram a propriedade de induzir a dimerização covalente de SOD1. No geral, os dados mostram que o DHA induz a agregação de SOD1, através de um processo envolvendo a exposição de superfícies hidrofóbicas, formação de pontes dissulfeto e também de possíveis cross-links envolvendo reações do tipo \"ene-tiol\". / ALS is a progressive and fatal disease caused by selective degeneration of motor neurons in the brain and spinal cord. Twenty percent of familial ALS (fALS) cases are caused mainly by point mutations in the sod1 gene. Docosahexaenoic acid (C22:6, n-3, DHA) is a highly unsaturated fatty acid, wich is one of the main fatty acids in the cerebral gray matter. Studies have linked SOD1 mutations to the formation of aggregates that could be induced by unsaturated fatty acids. The aim of this study was to evaluate the effect of DHA on aggregation of SOD1 fALS mutants in vitro and its mechanisms. CD analysis shows changes in the secondary structure of both apo-SOD1WT and G93A promoted by DHA resulting in an increase in the surface hydrophobicity and formation of structures such as beta amyloid, which was also confirmed by bis-ANS assay and Thioflavin, respectively. These changes enhance the interaction of SOD1 and DHA, leading to amorphous aggregates as revealed by FESEM. Incubation of DHA with apo-SOD1 forms results in high-molecular weight species as detected by SDS-PAGE analyses under non-reducing conditions and also by size exclusion chromatography. This appears to require Cys residues in their thiolate forms because high aggregates are not observed under reducing conditions and also by size exclusion chromatography or at acidic pH. Also, size-exclusion chromatography indicates that the mutant apo-SOD1 aggregation is dependent on the unsaturation and cis-conformation of fatty acids. Compared to the DHA, DHAOOH had a minor effect on SOD1 aggregation, however revealed the ability to induce covalent dimerization of SOD1. Overall, the data suggest a mechanism of DHA aggregation, by a process involving exposure to hydrophobic surfaces, formation of disulfide bonds and also for possible cross-links involving reactions such \"thiol-ene\".

TRAIL (TNF-Related Apoptosis Inducing Ligand) et CD40 Ligand, membre de la superfamille (SF) du TNF (Tumor Necrosis Factor) apparaissent comme des cibles attractives pour la thérapie ciblée du cancer. Une caractéristique commune des membres de la SF-TNF est la structure homotrimérique du ligand qui oligomérise les récepteurs pour induire la signalisation cellulaire. Cette interaction multivalente entre ligands et récepteurs est déterminante dans l’induction de la réponse cellulaire. L’objectif de cette thèse est de i) développer des ligands multivalents de TRAIL-R2 et CD40 afin d’améliorer leur efficacité anti-tumorale puis de les associer dans des stratégies anti-tumorales innovantes et ii) de caractériser les interactions entre ces ligands et les récepteurs à la surface de la cellule pour comprendre l’impact de l’oligomerisation sur l’initiation de l’apoptose au niveau membranaire.Ainsi nous avons utilisé des peptides cycliques spécifiques du récepteur de TRAIL-R2 (TRAILmim/DR5) que nous avons multimérisés sur des plateformes chimiques innovantes. Nous nous sommes également intéressés à l’état d’oligomérisation des récepteurs avant leur contact avec le ligand dans le but de mieux comprendre les interactions multivalentes. Enfin, nous avons caractérisé à l’aide de la technique de résonance plasmonique de surface et d’un biocapteur basé sur la fluorescence les interactions entre ces ligands multivalents et le récepteur TRAIL-R2. Ces travaux nous ont donc montré la nécessité d’analyser les interactions entre ligands et récepteurs directement à la surface de la cellule pour améliorer le développement de ligands pro apoptotiques efficaces. / TRAIL (TNF- Related Apoptosis Inducing Ligand) and CD40Ligand, members of the superfamily (SF) of TNF (Tumor Necrosis Factor), appear as attractive targets for cancer therapy. A common feature of members of the TNF-SF is the homotrimeric structure that oligomerized their receptors to induce cell signaling. This multivalent interaction between ligands and receptors is crucial for apoptosis induction.The aims of this thesis is to i) develop multivalent ligands of TRAIL -R2 and CD40 to enhance their antitumor efficacy and to associate them in innovative strategies and ii) to characterize the interactions between ligands and receptors at cell surface to understand the impact of oligomerization on the initiation of apoptosis at membrane level.We used cyclic peptides specific of TRAIL-R2 (TRAILmim/DR5) that we multimerized on innovative chemical scaffolds. We also interested in the state of receptor oligomerization before their contact with the ligand in order to better understand the multivalent interactions. Finally, we characterized using the technique of surface plasmon resonance and biosensor based fluorescence interactions between multivalent ligands and TRAIL- R2.In this work we showed the need to analyze the interactions between ligands and receptors directly on the surface of the cell to improve the development of effective pro -apoptotic ligands.

Ce travail décrit la synthèse et l’étude structurale d’oligomères mixtes linéaires et cycliques, alternant des liens amides et N-aminoamides, nommés 1 :1-[a/a-N-amino]mères. Le premier chapitre est consacré à l’étude bibliographique des méthodes de cyclisation des peptides et pseudopeptides ainsi qu’à leurs nombreuses applications. Il a été décrit que l’incorporation d’éléments potentiellement structurants, comme l’introduction de modifications du squelette peptidique, pourrait faciliter la cyclisation des oligomères linéaires. Dans cette optique, l’exploitation de travaux antérieurs du laboratoire, exposée dans le deuxième chapitre, a donné accès à de nouveaux 1 :1-[a/a-N-amino]mères phtaloylés, puis aux premiers cyclo-1 :1-[a/a-N-amino]mères protégés. La déprotection du groupement phtalimide d’un de ces composés cycliques ouvre de nouvelles perspectives comme la fonctionnalisation de l’atome d’azote déprotégé. Le troisième chapitre résume les analyses structurales réalisées et met principalement en avant les conformations originales qu’adoptent ces différents oligomères ainsi que l’influence du lien N-aminoamide. Les structures ont été établies grâce à une approche complète associant plusieurs techniques spectroscopiques (RMN, IR, fluorescence et diffraction des rayons X). Par exemple, l’analyse par diffraction des rayons X a permis de mettre en évidence la formation de nanotubes due à un empilement original de cyclotétramères déprotégés. / This work describes the synthesis and the structural study of linear and cyclic mixed oligomers alternating N-aminoamide and amide bonds, named 1:1-[a/a-N-amino]mers. The first chapter is a bibliographic study on cyclization methods of peptides and pseudopeptides (backbone modified peptides) and their applications. It has been described that the incorporation of potential structural elements, like introduction of changes to peptide backbone, could be facilitating the cyclization of linear oligomers. With this in mind, the use of previous work in our laboratory, discussed in the second chapter, gives access to new phtaloylated 1:1-[a/a-N-amino]mers and also to the first protected cyclo-1:1-[a/a-N-amino]mers. The deprotection of phthalimid group of one of these cyclic compounds opens up new opportunities like functionalization of the deprotected nitrogen atom. The third chapter sums up the results of the structural analyses and principally highlights the original conformations adopted by these different oligomers and the influence of the N-aminoamide bond. The structures were established through a complete study using several spectroscopic techniques (NMR, IR, fluorescence, X-ray crystallography). For example, the X ray studies highlight the formation of nanotubes through an original self-assembling of deprotected cyclotetramers.