Chemical Biology Research

In the group of Prof Rob Liskamp, Chemistry is applied as a powerful “enabling” science in Chemical Biology facilitating developments in biology and the medical sciences. Core to chemistry is the design and creation of molecules allowing us to obtain insights in biological processes including diseases such as cancer, infections, and autoimmune diseases leading to new approaches of treatment. It requires a multidisciplinary effort where chemical biologists, cancer researchers, physicists, and structural chemists are collaborating. Despite enormous advances, vaccines for malaria, HIV, and hepatitis C are still not available while resistance against antibiotics is increasing. We are developing chemosynthetic vaccines based on essential parts of proteins of a virus. Using molecular evolutionary approaches, we are developing a new generation of smaller (synthetic) antibodies for treatment of inflammation, infections, and cancer.

Peptido sulfonyl fluorides as proteasome inhibitors as potential anti-cancer agents, as well as inhibitors of other crucial proteases. We have found that the proteasome, which is essential for quality control of proteins in normal, cancer or infected cells, can be inhibited by compounds containing the novel sulfonyl fluoride warhead. The activity of the thus obtained peptido sulfonyl fluorides can be tuned by varying the amino acid residues, the N-terminal (protective) group and the amino sulfonyl fluoride moiety. In this way very active (figure) and very selective proteasome inhibitors, but also inhibitors of other (serine) proteases, can be obtained. In addition, these compounds may be used as molecular probes in proteomics studies for finding new proteases/hydrolases. The aim of the research is to design, synthesize and evaluate new proteasome inhibitors and inhibitors of other proteases

New warheads and anti-microbial peptides. The sulfonyl fluoride warhead has led to the development of other novel warheads. These will be explored for incorporation into peptide and peptidomimetic sequences leading to new inhibitors of cysteine protease and protein phosphatase inhibitors, which are involved in cancer. In addition, a variety of warheads will be combined with anti-microbial peptides leading to novel hybrid-antibiotics, which may be important for tackling resistance of microbes against existing antibiotics.

Protein mimics for development of synthetic vaccines and synthetic antibodies In contrast to proteins, protein mimics will be drastically smaller, thereby endowing them with highly desirable properties such as a broad and convenient accessibility by notably chemosynthesis and/or biosynthesis as well as defined and tuneable biological properties. Their smaller size will also lead to reduction of undesired properties including the elimination of immunogenic sites and segments that are for example readily cleaved by proteolysis. In addition, the reduced size will facilitate administration of these biologically active mimics. These molecular constructs pose enormous challenges with respect to design and construction to adequately and effectively mimic the structural and biological properties of proteins. Research aims are approaches for new classes of artificial proteins and synthetic vaccines by mimicry and scaffold-assembly of discontinuous epitopes. Discontinuous epitopes play a dominant role in many protein-protein interactions including those involved in antigen-antibody interactions (figure).

Tunable self-assembly hydrogel network systems and surfaces for storage and adherence of cells. In the past we have shown that (small) peptides involved in diseases gave rise to the formation of aggregates or peptides gels. We know wish to use the aggregative properties of these peptides to our advantage by developing and synthesizing peptide molecular constructs for storage of cells and organoids. Research aims are therefore the development of three component molecular construct consisting of a (1) self assembly peptide, a (2) hydrophilic spacer and an (3) extra cellular matrix (ECM) peptide. Another research aim is new surface chemistry for coating of surfaces of plates for selective adherence of different cell-types simultaneously. This may represent first steps to obtain multi-different-cell constructs as is the case in organs and primitive multicellular life forms.

Chemoproteomic approaches to identify protein targets of pathogenic toxins A large number of bacterial pathogens produce toxins that modify host cell function, initially via interaction with specific cell surface proteins. Molecular characterisation of such interactions is usually hampered by their transient nature. An increasingly powerful approach is therefore the use of molecular probes to achieve irreversible binding. These molecules are composed of (1) a ligand; in this case the toxin, (2) an affinity label for irreversible binding to the receptor and (3) a fishing tag for isolating the captured ligand-receptor complex. These trivalent probes will be used in combination with quantitative mass-spectrometry for molecular characterisation of ligand-receptor interactions.