The focus of our research is on the exploration and inhibition of protein-protein interactions based on synthetic mimicry of protein binding sites. The ultimate goal is to modulate protein function through controlled interference with the underlying molecular interactions.
Essentially all biological processes are based on specific binding events, which are initiated by molecular recognition between biomacromolecules, in particular proteins. The design and generation of molecules, which can mimic the binding and/or functional sites of proteins, represents a promising strategy for the exploration an understanding of protein structure and function. In addition to this basic significance, such proteinmimetics are also useful tools for a range of biomedical applications, particularly the development of inhibitors of protein-protein interactions.
Inhibition of a protein-protein interaction through a binding site mimetic.
- Development of synthetic (solid-phase synthesis) and biochemical (direct and competitive binding assays) methods for the generation and evaluation of scaffolded and assembled peptides, in which protein fragments are presented through a molecular scaffold in a discontinuous and nonlinear fashion, as mimetics of protein binding sites.
- Design, generation, evaluation of binding affinities and specificities of scaffolded and/or assembled peptides as synthetic mimetics of binding sites of biomedically relevant proteins. The protein-protein interactions we study include the following:
- The interaction of the HIV-1 envelope protein gp120 with its cellular receptors CD4 and the coreceptor CXCR4 (a member of the GPCR family of receptors)
- The interaction of protein domains (hYAP-WW, Mena EVH1) with proline-rich ligands
- The interaction of the cytokine receptor gp130 with viral interleukin-6
- Acetylcholine esterase: Interaction with Inhibitor (fasciculin-2)
Generation of scaffolded peptides as protein binding site mimetics.
Synthetic mimetics of the CD4-binding site of HIV gp120 are immunogen candidates for the elicitation of anti-HIV-1 antibodies.