Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization

Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clustering a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs

Inside glandular trichomes : pleiotropic drug resistance transporters in Artemisia annua and specialized metabolism in Nicotiana tabacum

The secondary metabolism is highly active in plant glandular trichomes, which have therefore been extensively studied to elucidate the related biosynthetic pathways. In contrast, the transport of secondary metabolites remains poorly understood. In this work, we developed tools to study enzymes involved in the synthesis and secretion of secondary metabolites in trichomes of Artemisia annua and Nicotiana tabacum. A. annua glandular trichomes produce the sesquiterpene artemisinin, a strong antimalarial drug. However how this molecule is secreted out of the trichomes is unknown. As several Pleiotropic Drug Resistance (PDR) transporters are involved in diterpenes transport, we made the hypothesis that this sesquiterpene might also be transported by a PDR transporter. We identified 15 putative A. annua PDR genes in the DNA databases. Two of them, AaPDR1 and AaPDR2, were found to be highly expressed in trichomes. Their cDNAs were cloned and their expression in heterologous and homologous systems was investigated in order to study their transport activity. However, the role of AaPDR2 might be to transport other sesquiterpene(s) than artemisinin since it is expressed in T-shaped trichomes which, unlike glandular trichomes, do not synthesize artemisinin. N. tabacum bears two types of glandular trichomes, short glandular trichomes (SGTs) and tall glandular trichomes (TGTs). TGTs have been largely studied and are known to produce diterpenes and sugar esters, which are the main compounds of the trichome exudate. In contrast, SGTs have been poorly characterized. Using centrifugation on Percoll density gradients, we set up a method to obtain samples enriched in tall and short trichomes with a purity of 93% and 86%, respectively. The proteomes of these samples were compared by mass spectrometry using a quantitative methodology (isobaric tags for relative and absolute quantitation), which led to the identification of 461 protein groups. TGTs specifically contain enzymes involved in diterpenes and lipids biosynthesis. Proteins that are more abundant in SGTs belong to the translation machinery (ribosomal proteins), primary metabolism (phosphoenolpyruvate carboxykinase, alanine or aspartate amino transferases) or secondary metabolism (polyphenol oxidase). These data open the way to more focused approaches aimed at deciphering the physiological roles of SGTs.(AGRO - Sciences agronomiques et ingénierie biologique) -- UCL, 201

Utilisation de polymères dans la libération contrôlée de principes actifs médicamenteux

Doctorat en sciences chimiques -- UCL, 199

Activité de la chymotrypsine et activation de son zymogène, natifs ou modifiés, en micelles inverses et en solvants organiques

Doctorat en sciences chimiques -- UCL, 199

Amélioration de la fertilité du sol en maraîchage Retour du cycle de formations organisé durant l'hiver 2016 (suite de l'Itinéraires BIO 28)

Retour du cycle de formations organisé durant l'hiver 2016 (suite de l'Itinéraires BIO 28): fertilité biologique et physique du sol en maraîchage biologique, comment adapter son travail de sol - et donc le choix de ses outils - en fonction des notions de base vues sur la fertilité du sol et les contraintes liées au maraîchag

Amélioration de la fertilité du sol en maraichage Retour du cycle de formation organisé durant l'hiver 2016

Retour du cycle de formation organisé durant l'hiver 2016: François et Brigitte Dereppe, 30 ans de maraichage sur 60 ares: une histoire de minutie qui a bien tourné; le carbone: clé des pratiques agroécologiques en maraichage, par Konrad Schreiber; conférence sur les intercultures et la réduction du travail du sol par Victor Leforestier (suite dans Itinéraires BIO 29

Du maraîchage sur sol vivant sans apport d'azote Compte-rendu de la visite du jardin des Peltier à Breteuil-sur-Iton, le 11 juillet 2016

Depuis plus de 8 ans, Daniel et Françoise Mulet produisent des légumes bio avec très peu d'apports d'azote, seulement des apports de matières organiques riches en carbone. Le secret de la réussite: pas de travail du sol pour le développement intensif de la vie du sol. En résumé, un jardin de production de légumes pas comme les autres! Ces deux frères cultivent des légumes sur plus d'un hectare et 600m² de serres, dans une ferme de 9 hectares située au cœur de la Normandie, dans l'Eure, à Breteuil-sur-Iton, et tout cela dans un cadre bien bucolique

Modification chimique du lysozyme par le 2,4-di(chlorosulfonyl)-ph nol

SIGLEBSE B226054Y / UCL - Université Catholique de LouvainBEBelgiu