Raphael Franzini

Assistant Professor of Medicinal Chemistry and
Adjunct Assistant Professor of Internal Medicine

Franzini Photo

M.S. Swiss Federal Institute of Technology, Lausanne, Switzerland

Ph.D. Stanford University

Research

References

raphael.franzini@utah.edu

Raphael Franzini's Lab Page

Raphael Franzini's Google Scholar List

 

Biological Chemistry Program

Drug development, chemical probes, imaging agents

Research

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.

Fig 1

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.

Fig 2

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.

Fig 3

Figure 3. Schematic representation of binary molecular probes.

References

Encoded Libraries in Drug Discovery and Chemical Biology:

  1. Lik Hang Yuen, and Raphael M. Franzini, Achievements, Challenges, and Opportunities in DNA‐Encoded Library Research: An Academic Point of View, ChemBioChem, 2017, 18, 829. (http://onlinelibrary.wiley.com/doi/10.1002/cbic.201600567/full)
  1. Lik Hang Yuen, and Raphael M. Franzini, Stability of Oligonucleotide–Small Molecule Conjugates to DNA-Deprotection Conditions, Bioconjugate Chem., 2017, 28, 1076. (http://pubs.acs.org/doi/abs/10.1021/acs.bioconjchem.7b00005)
  1. Raphael M. Franzini, and Cassie Randolph, Chemical Space of DNA-encoded Chemical Libraries, Med. Chem., 2016, 59, 6629. (http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01874)
  1. Florent Samain, Torun Ekblad, Gediminas Mikutis, Nan Zhong, Angela Nauer, Davor Bajic, Jörg Scheuermann, Peter J. Brown, Susanne Gräslund, Herwig Schüler, Dario Neri, and Raphael M. Franzini, Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-encoded Chemical Library, Med. Chem., 2015, 58, 5143. (http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00432)
  1. Raphael M. Franzini, Angela Nauer, Jörg Scheuermann, and Dario Neri, Interrogating Target-Specificity by Parallel Screening of a DNA-Encoded Chemical Library against Closely Related Proteins, Commun., 2015, 51, 8014. (http://pubs.rsc.org/en/Content/ArticleLanding/2015/CC/C5CC01230A#!divAbstract)
  1. Raphael M. Franzini, Torun Ekblad, Nan Zhong, Moreno Wichert, Willy Decurtins, Angela Nauer, Jörg Scheuermann, Mauro Zimmermann, Peter J. Brown, Jonathan Hall, Susanne Gräslund, Herwig Schüler, and Dario Neri, Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA-Encoded Chemical Library, Chem. Int. Ed., 2015, 127, 3999. (http://onlinelibrary.wiley.com/doi/10.1002/anie.201410736/full)

Targeted Therapeutics and Imaging Agents:

  1. Minghao Xu, Julian Tu, and Raphael M. Franzini, Rapid and efficient tetrazine-induced drug release from highly stable benzonorbornadiene derivatives, Commun., 2017, 53, 6271. (http://pubs.rsc.org/en/Content/ArticleLanding/2017/CC/C7CC03477F#!divAbstract)
  1. Moreno Wichert, Nikolaus Krall, Willy Decurtins, Raphael M Franzini, Francesca Pretto, Petra Schneider, Dario Neri, and Jörg Scheuermann, Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation, Chem., 2015, 7, 241. (http://www.nature.com/nchem/journal/v7/n3/full/nchem.2158.html?foxtrotcallback=true)

Binary Molecular Probes:

  1. Raphael M. Franzini and Eric T. Kool, Improved Templated Fluorogenic Probes Enhance the Analysis of Closely Related Pathogenic Bacteria by Microscopy and Flow Cytometry, Bioconjugate Chem.2011, 22, 1869. (http://pubs.acs.org/doi/abs/10.1021/bc2003567)
  1. Raphael M. Franzini and Eric T. Kool, Two Successive Reactions on a DNA Template: A Strategy for Improving Background Fluorescence and Specificity in Nucleic Acid Detection, Eur. J., 2011, 17, 2168. (http://onlinelibrary.wiley.com/doi/10.1002/chem.201002426/abstract)
  1. Raphael M. Franzini and Eric T. Kool, Efficient Nucleic Acid Detection by Templated Reductive Quencher Release, Am. Chem. Soc., 2009, 131, 16021. (http://pubs.acs.org/doi/abs/10.1021/ja904138v)

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Last Updated: 8/11/17