Research

Chemical Biology in Drug and Vaccine Discovery

The main aim is to develop methods to exploit the fast growing database of 3D structural information on proteins, protein-protein complexes, and protein-nucleic acid complexes, for the design of novel folded biologically active protein epitope mimetics (PEMs). The mimetics should provide access to molecules able to target specific surface sites (epitopes) on proteins, and so act as inhibitors of protein-protein interactions, or protein-nucleic acid interactions, or as epitope mimetics able to stimulate adaptive immune responses. We are interested in the design and synthesis of novel peptidomimetic building blocks that stabilize secondary structure motifs (such as alpha-helices, ß-turns, ß-strands and ß-hairpins).

A ß-hairpin antibiotic targeting pseudomonas spp. discovered in earlier work.

In one project, we have discovered a new family of peptidomimetic molecules with potent antimicrobial activity against Gram-negative bacteria. These antibiotics arose from efforts to design mimetics of naturally occurring cationic host-defense peptides. The most active mimetics show activity against pseudomonas spp. in the low nanomolar range. Current research has shown that this new family of antibiotics has a novel mechanism of action, targeting the outer membrane (OM) protein LptD essential for the assembly of the outer cell membrane in Gram-negative bacteria. A detailed study of how the antibiotics interact with LptD is currently ongoing. Other related molecules have recently been discovered that target other essential OM proteins in Gram-negative bacteria.

Target of the ß-hairpin antibiotic, the OM proteins LptD/E (blue-green/orange), shown transporting LPS (purple) to the bacterial cell surface.

In another study, we designed cyclic β-hairpin-shaped mimetics that bind to RNA, in particular, folded RNA motifs such as the TAR and RRE recognition elements, which are important for the life cycle of HIV-1. Structural studies have already revealed how these peptidomimetics interact with their RNA targets.

Structure of a PEM bound to TAR RNA.

The field of vaccine design is now entering the era of "structural vaccinology", where 3D structural information on host-derived neutralizing monoclonal antibodies bound to their target antigens is being used in efforts to design potential vaccine candidates. Protein engineers are trying to develop approaches to potential protein-based antigens as vaccine candidates. In our work, we are exploring a synthetic chemistry-based approach to vaccine design. We exploit the 3D structural information to design synthetic epitope mimetics as vaccine candidates. We have also introduced a novel nanoparticle delivery system (called "Synthetic Virus-Like Particles" (SVLPs)), to deliver such epitope mimetics to the immune system and so elicit strong protective immune responses. Current projects involve efforts to develop anti-viral vaccines targeting HIV-1 and RSV, as well as a protective vaccine against the malaria parasite Plasmodium falciparum.

A synthetic malaria vaccine candidate, with the virosome delivery system developed by Berna Biotech, tested in clinical trials in Europe and Africa.