Multivalent interactions are common in nature, such as influenza virus infecting epithelial cells, clearance of pathogens by antibody-mediated attachment to macrophages, etc. To mimic nature, we utilized a bottom-up approach to develop various multivalent self-assembling systems based on leucine-zipper peptides. We tethered several pairs of leucine-zipper peptides to PAMAM dendrimers to form leucine-zipper dendrimers (LZDs). We conjugated Fos/Jun to the dendrimer to make D0Fos4 and D0Jun4, and studied the interactions between these LZDs and their cognate peptide target, either Jun or Fos. Our experiments showed that the D0Fos4 can non-covalently assemble four copies of Jun, and this approach can be further used for the rapid non-covalently assembling of multimeric ligands. We also pursued the multivalent target of GPCRs with a Fos/Jun assembly, and found the complex can potentially be used as a molecular switch to target GPCRs with controlled ligand activity. In a related project for bio-material design based on self-assembly of LZDs, we synthesized a different pair of LZDs, D-Ez4 and D-Kz4, and established that they can assemble at neutral pH to form helical fibrils which display higher order self-organized structures, providing a new methodology for bio-material design. In another effort for studying multivalent interactions, we conjugated three copies of the F23, mini-protein that binds the HIV-1 capsid protein, to a trimesic acid and obtained a trivalent inhibitor, Tri-F23. Tri-F23 showed enhanced binding in ELISA against gp120, but was not significantly more effective preventing HIV entry. This methodology provides a new strategy for developing multivalent inhibitors for preventing HIV-1 infection at the entry level. In a related area, we are developing imaging agents based on quantum dots that can detect GPCRs on whole cells and at the single molecule level. To this end, a new method was developed for biocompatible amphphilic polymers to coat quantum dots. This amphiphilic polymer facilitates rapid quantum dot conjugation to any ligand with a free thiol or engineered cysteine. Several GPCR targeted peptides have been utilized for imaging receptors on whole cells and as single molecules. These efforts will guide the rational design of multivalent ligands for targeting GPCRs and other cell surface proteins.

Notre étude aborde deux points importants sur les interactions supramoléculaires dans les polymères : tout d'abord comment des polymères peuvent s'assembler sur des surfaces planes au moyen de d'interactions de type hôte/invité, puis sur les interactions entre polymères à l'échelle de la molécule unique. En particulier nous verrons comment ces interactions à courte portée influent sur l'adhésion des chaînes sur des surfaces chimiquement contrôlées. Notre choix s'est porté sur un polymère d'origine naturelle le chitosane fonctionnalisé respectivement par des B-cyclodextrines (hôte) et des adamantanes (invité) et dont les assemblages forment des gels. Dans une première partie nous montrerons la possibilité de créer des multicouches de polymère par la méthode Layer-by-Layer (LbL) à l'aide des interactions de type hôte/invité, assemblage toutefois limité par les interactions électrostatiques au sein de la structure. Dans une seconde partie nous étudions les interactions multivalentes hôte/invité entre les couches de polymères en mesurant la force d'interaction par AFM. Nous avons pu mettre en évidence les différentes contributions à la force d'interaction et montrer que les interactions hôte//invités dominent les interactions non spécifiques d'un ordre de grandeur / In this study we focused on two important points concerning supramolecular interactions in polymeric systems. First; how polymers self-assemble on planar surfaces through side-chain host-guest interactions. Second; how those polymers interact each other at the level of single chain and how the adhesion properties of polymers on the modified surfaces can be controlled with those short ranged specific interactions. For that purpose a natural polysaccharide, chitosan, was chosen as the polymeric backbone and was specifically modified with host (B-cyclodextrin) and guest (adamanatane) molecules. It is known that those modified polysaccharides interact each other through host-guest units and their supramolecular assemblies exhibiting a gel-like behavior in solution state. In the first part of the study we investigated the feasibility to use supramolecular interactions to construct functional polymer multilayers by using the Layer-by-Layer (LbL) self assembly approach. The driving force with the proposed system is host-guest interactions thus short ranged and sterically demanding as the structural fitting is necessary. Our results show that multiple host-guest interactions along the chitosan chain allow the self assembles of the modified chitosans on guest-attached surfaces. The number of layers is limited and possibly affected by the electrostatic charge of the chitosan backbone. In the second part of the study we used atomic force microscope (AFM) to probe the multivalent host-guest interactions between modified polymer layers by direct force measurement. By this technique, the main contributions to the interaction between modified chitosan layers could be identified. Adhesion properties of the modified chitosans have also been investigated. The work of adhesion is about an order of magnitude larger for those chitosan derivatives that can form host-guest complexes than for those where this is not possible.