Raphael Franzini

Addressing the current challenges faced by clinicians will require an interdisciplinary approach combining knowledge of diverse fields. This research group especially focuses on the interfaces of Chemistry, Biology and Medicine with the aim of developing novel types of therapeutic agents, imaging probes and diagnostic assays. Standard experimental techniques used to achieve this goal include synthetic organic chemistry, instrumental analysis, and basic molecular biology methods. Three clusters of prospective research projects are outlined below.

Research activities are designed with keeping in mind the training objective for students and scientists in the group and aiming to provide a scientific environment that simultaneously encourages the realization of cutting-edge research and the advancement of each group member towards their professional goals.

Encoded Libraries in Drug Discovery and Chemical Biology
DNA-encoded libraries are collections of compounds in which each small molecule is uniquely encoded by a covalently linked DNA sequence. Panning encoded libraries for the protein of interest enriches target-binding molecules and high-throughput sequencing of the DNA-barcodes enable the straightforward identification of the corresponding structures. Encoded library technology allows screening ultra-large compound collections in a one-pot protocol. This technology has therefore the potential to drastically reduce time and expenses associated with hit discovery. Numerous hits against biologically relevant targets have been identified using encoded libraries and DNA-encoded library technology is becoming routinely implemented in drug discovery.

Our group is interested to further advance DNA-encoded library technology and to apply such libraries in chemical biology research and drug discovery. In addition to setting up a platform of libraries and screening them for drug candidates, we aim to expand this technology beyond the identification of affinity ligands and to constantly improve methodologies for library synthesis, encoding and screening.

Figure 1. Example of a screening result for a DNA-encoded chemical library with the general structure shown in the cartoon. Numbers on the x-/y-axis identify the chemical entities at the two diversity elements indicated by colored circles. The height of the individual bars represents the frequency with which a specific sequence has been identified as a measurement of binding to the target of interest. Compounds with elevated sequence counts are further evaluated for their activity towards the tested target.

Targeted Therapeutics and Imaging Agents
Targeting specific cell markers enables the localization of molecular entities at the site of disease. Such molecular targeting agents have great translational potential for applications in medicine, for examples as advanced therapeutic or imaging agents. Numerous examples of ongoing clinical trials underline the promise of such probes for future uses in medicine. Our group aims to develop technologies to enhance the properties of targeting molecules (e. g. biodistribution) as well as to identify novel avenues of translating disease-specific localization into a therapeutic effect or imaging readout.

Figure 2. Specific localization of molecules at the site of disease can be used for a variety of applications in medicine.

Binary Molecular Probes
Binary molecular probes are pairs of molecular entities both consisting of a recognition and a reporter element. The recognition elements bind to a common target and form a ternary complex with the analyte. Proximity-mediated interactions between the reporter elements then result in the anticipated downstream event.

Binary molecular probes are highly modular systems. For instance, different recognition elements (e. g. small-molecule ligands, nucleic acid hybridization sequences, antibodies, aptamers) are available enabling to target diverse analytes (e. g. proteins, nucleic acids, metabolites). Additionally, diverse reporter elements may be considered (e. g. reactive chemical groups, split-protein fragments, trans-splicing RNA/DNA, FRET pairs) providing diverse downstream events (e. g. fluorescence or bioluminescence signal, drug release). This modularity allows for the conception of molecular probes that can be tailor-made to a large number of problems within the life sciences and with high potential for clinical translation. Our group is interested in developing novel binary reactive probes and with potential applications in biosensing, imaging and advanced therapeutics.

Figure 3. Schematic representation of binary molecular probes.