Foldamères peptidomimétiques à base d'urées (vers le développement de structures complexes mimes d'architectures biologiques)

La fonction d une protéine dépend dans une large mesure de sa structure tridimensionnelle, c est pourquoi de nombreux chercheurs se sont passionnés pour la synthèse des foldamères, molécules de synthèse, bioinspirées, capables d adopter des structures repliées bien définies. Parmi les différentes classes de foldamères, les oligourées aliphatiques étudiées dans notre laboratoire s organisent pour former des structures hélicoïdales voisines de l hélice a des polypeptides naturels. Pour développer des hélices fonctionnelles mimes de structures biologiques, il est intéressant de mieux comprendre les règles de leur repliement, par exemple en modifiant la nature des unités monomériques. Au cours de cette thèse, nous avons donc testé la compatibilité de la géométrie de l hélice d oligourée avec des résidus comportant de fortes contraintes stériques comme des groupements gem-diméthyles et des cycles pyrrolidines. En utilisant les résidus pyrrolidine, nous avons ensuite développé une nouvelle stratégie de synthèse par condensation de segments permettant de concevoir des hélices de grande taille (jusqu à 4 nm). Grâce à cette nouvelle stratégie de synthèse et aux informations obtenues sur la stabilité des hélices nous avons pu concevoir des architectures plus complexes (structures quaternaires) résultant de l assemblage programmé d hélices hydrosolubles.The biological functions of proteins are mainly correlated to their tridimensional structure. For this reason a large number of chemists are interested in the synthesis of foldamers, which are bioinspired artificial molecules possessing well-defined folded conformations. In particular, in our laboratories we focused on the study of oligourea foldamers, which form well-defined and remarkably stable helical structures, analogous to the natural polypeptides a-helix. In order to develop artificial functional helices able to mimic biological structures, it is interesting to understand the rules governing their folding, for example by comparing different residues substitution patterns. During this thesis we have investigated the compatibility of the helix geometry with residues containing steric constraints, such as gem-dimethylated units or pyrrolidine cycle. We have developed a new segment condensation strategy based on these residues, which enabled the facile synthesis of long helical segments (up to 4 nm). The use of this novel approach, combined with the information acquired on helical stability allowed us to produce more complex architectures (quaternary structures) resulting from the controlled assembly of water soluble helices.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Peptide-oligourea chimeric compounds and methods of their use

(EN) The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the invention relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the invention may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof

Structural Basis for alpha-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers

Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization

Principais Patologias Podais Em Asininos E As Suas Abordagens

Os Asininos são considerados animais rústicos porque têm elevada capacidade de adaptação a meios áridos. No entanto, podem ser afetados por diversas patologias, nomeadamente as patologias podais, se não forem adotados os cuidados necessários para garantir o bom estado dos cascos. Tal como os equinos, os asininos devem ter acesso a cuidados podais adequados, como ferração e/ou aparo de forma a garantir conforto, saúde, e bem-estar do casco. As patologias podais não devem ser negligenciadas porque são causa de claudicação, dor e desconforto. Esta dissertação visa abordar as principais patologias podais em asininos de forma a compreender as várias abordagens terapêuticas. Desta forma é importante conhecer a anatomia e fisiologia do casco saudável. Do ponto de vista anatómico, a estrutura interna do casco do asinino assemelha-se à do cavalo, mas tem particularidades distintas a nível da estrutura externa e também a nível funcional. Só após esta perceção é que se devem abordar as principais doenças podais em asininos, nomeadamente laminite, abcesso de casco, e formigueiro, descrevendo as diferentes terapêuticas. Atualmente existem várias abordagens terapêuticas não farmacológicas usadas isoladamente ou combinadas com medicação para auxiliar o tratamento farmacológico das patologias podais. Entre as mais recentemente citadas encontramos a hirudoterapia, homeopatia, fitoterapia, entre outras. O principal objetivo desta dissertação é a abordagem das técnicas terapêuticas ou auxiliares de terapia farmacológica, consideradas como mais recentes, de forma disponibilizar informação aos proprietários sobre estas terapias e assim utilizar os fármacos de forma mais adequada. A tese será uma revisão bibliográfica que incluirá uma revisão sobre a anatomia do casco dos asininos, por forma a facilitar a compreensão da abordagem das doenças podais mais frequentes, nomeadamente a laminite, o abcesso de casco, e o formigueiro.Donkeys are considered rustic animals because of their abilityto adapt in arid environments. However, they can be affected by various hoof pathologies, it they do not receive the necessary care to ensure the hooves’ good condition. Like horses, donkeys should have access to appropriate hoof care, such as shoeing and/or trimming, to ensure comfort, health, and well-being of the hoof. Foot pathologies should not be neglected because they cause of lameness, pain and discomfort. This work aims to address the main hoof pathologies in donkeys and understand the different therapeutic approaches. To better understand hoof pathologies, it is important to understand the anatomy and physiology of a healthy hoof. From an anatomical point of view, the internal structure of the donkey’s hoof resembles that of a horse, but it has differences in terms of external structure and functioning. Only after this comprehension should the main hoof diseases in donkeys be addressed, namely laminitis, hoof abscess, and white line disease, in order to describe the different therapeutic approaches. Currently, there are several non-pharmacological therapeutic approaches used alone or combined with medication to assist in the pharmaceutical treatment of hoof pathologies. Among the more recently cited ones, we find hydrotherapy, laser therapy, homeopathy, phytotherapy, among others. The main objective of this thesis is to address the most recent and appropriate therapeutic approaches. The dissertation is a literature review that will include the anatomy of donkeys’ hooves better understand the therapeutic approach to the most common hoof diseases, namely laminitis, hoof abscess, and white line disease

PEPTIDE-OLIGOUREA CHIMERIC COMPOUNDS AND METHODS OF THEIR USE

La présente invention porte sur des compositions et des procédés pour la production de composés oligomères thérapeutiques. Dans un autre aspect l'invention porte sur des procédés pour l'administration des composés oligomères pour le traitement et la prévention d'une maladie chez un mammifère. En particulier, l'invention porte sur des médicaments comprenant divers nouveaux composés oligomères et leurs sels pharmaceutiquement acceptables. Les composés selon l'invention peuvent éventuellement être administrés avec au moins un excipient pharmaceutiquement acceptable, un principe pharmacologiquement actif supplémentaire ou une association de ceux-ci.The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the invention relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the invention may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof

Synthesis and Folding Propensity of Aliphatic Oligoureas Containing Repeats of Proline-Type Units

The synthesis and conformational analysis of aliphatic oligoureas containing multiple adjacent <i>N</i>-alkylated units derived from proline (i.e., Pro^u) are reported. The insertion of trisubstituted ureas in the main chain of <i>N</i>,<i>N</i>′-linked oligourea foldamers locally impairs the characteristic three centered-hydrogen bonding pattern associated with the formation of 2.5-helical structures. Three series of oligomers have been studied: one series in which the Pro^u repeat is flanked on both sides by canonical urea residues (e.g., oligomers <b>2</b>–<b>6</b>), one series with canonical residues on either side of the Pro^u repeat (oligomers <b>12</b> and <b>23</b>), and one series consisting exclusively of Pro^u residues (oligomers <b>25</b> and <b>26</b>). Spectroscopic (NMR and electronic circular dichroism) and X-ray diffraction studies reveal that the 2.5-helix formed by oligomers of <i>N</i>,<i>N</i>′-disubstituted ureas is robust enough to accommodate short oligopyrrolidine segments (Pro^u)_<i>n</i> (<i>n</i> < 7) that alone display no intrinsic folding propensity

FOLDAMER HELIX BUNDLE-BASED MOLECULAR ENCAPSULATION

The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the disclosure relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof

Pro-drug peptide with improved pharmaceutical properties

The present disclosure relates to a pro-drug peptide, or a salt thereof, having improvement for at least one biological property relative to a parent peptide or peptidomimetic, wherein the biological property is selected from the group consisting of therapeutic index, stability, solubility, toxicity, adsorption, and pre-systemic metabolism. The pro-drug peptide comprising the following structure: Z-pep, wherein: pep is the parent peptide or peptidomimetic; Z is a sequence of n amino acids, Z is cleaved in vivo releasing pep; n≥2 amino acids. The present disclosure also relates to methods of making and using the pro-drug peptide of the present disclosure. For example, the present disclosure describes a pro-drug peptide that may be used to prevent, treat, or ameliorate at least one symptom of hypoglycemia or a hypoglycemia-related disease or disorder

QUATERNARY ASSEMBLIES OF WATER-SOLUBLE NON-PEPTIDE HELICAL FOLDAMERS, THEIR USE AND PRODUCTION THEREOF

The present description provides compositions and methods for producing therapeutic oligomeric compounds. In another aspect the description provides methods for administering the oligomeric compounds for the treatment and prevention of disease in a mammal. In particular, the disclosure relates to medicaments comprising various novel oligomeric compounds and pharmaceutically acceptable salts thereof. The compounds of the disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient, additional pharmacologically active agent or a combination thereof