
Raphael Franzini
CONTACT
Office
Skaggs Pharmacy Research Building
Room SRB 1926
Phone: (+1) 801-585-9051
Email:
Laboratory
Skaggs Pharmacy Research Building
Room SRB 1800
Phone: (+1) 801-587-3531
MedChem Office
Room 307 Skaggs Hall
Phone: (+1) 801-581-7063
Education
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M. Sc. 2005, Molecular and Biological Chemistry, EPFL
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Ph. D. 2010, Organic Chemistry, Stanford University - Research group of Prof. Eric Kool
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2012-2015, Postdoctoral Fellow, ETH Zurich - Research group of Prof. Dario Neri
Research Interests
DNA-encoded libraries: Streamlining drug discovery
One of the key steps in developing a new drug is to identify molecules that bind to a putative therapeutic target. However, there is a near-unlimited number of possible molecules and to identify the right one is a formidable challenge.
One approach to achieve this goal is to tag compounds with DNA strands whose sequence encodes for the structure of each compounds. In this way it is possible to use target proteins immobilized on surfaces as baits to fish for compounds that bind to this protein. Sequencing the attached DNA codes then allows to identify the corresponding molecules. In fact, this approach provides a semi-quantitative estimation of the target affinity of each compound in the library.
Such DNA-encoded libraries are nowadays used routinely in drug discovery at pharmaceutical companies. However, the prospect of this method remains largely untapped in academic medicinal chemistry efforts because of the costs associated with generating large library platforms and the validation of multiple hit compounds. We aim to overcome this problem by generating libraries that are structurally designed with specific protein families in mind. In this way, we can achieve consistent screening success at a fraction of the costs of large one-fit-all DNA-encoded library platforms.
Using such libraries, we were able to discover high potency hit compounds for several enzymes with speed and cost-efficiency unachievable by conventional methods. In parallel, we aim to further our understanding of how to synthesize and design such library and to develop algorithms for extracting important structural data from such library screens.


Dissociative Bioorthogonal Chemistry: Activating drugs and probes on demand
Reactions between non-biological reagents that occur readily in biological systems without being disturbed by it are called bioorthogonal. Numerous bioorthogonal reactions have been developed with a focus on reactions that link two molecules together. Although less well established, bioorthogonal reactions that dissociate and release a molecule could find widespread applications in molecular tools for biological research, the development of diagnostics, and the design of innovative therapeutics.
A key focus of the Franzini group is the development of such reactions that can release molecules inside cells or living organisms. Reactions thus discovered will then be applied to the development of tools to study cellular processes and new targeted therapeutics for cancer therapy.
Lab Information

Alba L. Montoya Arias
Ph.D. University of Texas at El Paso
M. Sc. Universidad del Valle

Titas Zeb
M. Sc. National Institute of Pharmaceutical Education and Research
B. Sc. Gupta College of Technical Sciences

Brayden Halverson
B. Sc. University of Utah

Dennis Morgan III

Julian Tu
Current position: Postdoc in the group of Amy Barrios at the University of Utah
B. Sc. University of California at Santa Barbara

Srikanta Dana
Current position: Scientist at TGen
Ph. D. Jawaharlal Neru University, M. Sc. Bengal Science and Engineering University

Minghao Xu
Current position: Scientist in group of M. G. Finn at Georgia Tech
B. Sc. & Ph. D. East China University of Science and Technology

Lik Hang (Herman) Yuen
Current position: Senior II, Nurix
Ph. D Stanford University
B. Sc. University of California at Berkeley

Nicole Rueb
Current position: Barrios Group, University of Utah
B. Sc. University of Idaho

Randy Galan
Current position: Medical Student at Penn State College of Medicine University

Sara Augustine
Current position: Graduate student, UC Irvine
High-School Summer Students
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Heejoon Jeon (Summer 2019; West High)
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Elise Perry (Summer 2019; Juan Diego)
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Mihal Odrobina (Summer 2019; Waterford; University of Pennsylvania)
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Tejita Agarwal (Summers 2016-2018; West High; Yale University)
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Ethan Lamé (Summer 2018; Juan Diego)
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Eric Zimmerman (Summer 2017; Waterford; University of Pennsylvania)
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Ayden Carbaugh (Summer 2017; Juan Diego)
Opportunities
Please email Dr. Raphael Franzini for inquiries or information.
Publications
2021
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"Mechanisms and Substituent Effects of Metal-Free Bioorthogonal Reactions" T. Deb, J. Tu, R. M. Franzini. Chem. Rev., 2021, in press. [Article]
2020
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"Integrating DNA-encoded Chemical Libraries with Virtual Combinatorial Library Screening: Optimizing a PARP10 Inhibitor" M. Lemke, H. Ravenscroft, N. J. Rueb, D. Kireev, D. Ferraris, R. M. Franzini. Bioorg. Med. Chem. Letts., 2020, 30, 127464. [Article]
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"A Stable Precursor for Bioorthogonally Removable 3-Isocyanopropyloxycarbonyl (ICPrc) Protecting Groups" J. Tu, M. Xu, R. M. Franzini. Synlett, 2020, 31, 1701-1704. [Article]
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"The Unique Bioorthogonal Chemistry of Isonitriles" T. Deb, R. M. Franzini. Synlett, 2020, 31, 938-944.
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"Isonitrile-responsive and Bioorthogonally Removable Tetrazine Protecting Groups" J. Tu, D. Svatunek, S. Parvez, H. J. Eckvahl, M. Xu, R. T. Peterson, K. N. Houk, R. M. Franzini . Chem. Sci. 2020, 11, 169-179. [Article]
2019
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"Tuning Isonitrile/Tetrazine Chemistry for Accelerated Deprotection and Formation of Stable Conjugates" M. Xu, T. Deb, J. Tu, R. M. Franzini. J. Org. Chem. 2019, 84, 15520-15529. [Article]
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"Stable, Reactive and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles" J. Tu, D. Svatunek, S. Parvez, A. C. Liu, B. Levandowski, H. J. Eckvahl, R. T. Peterson, K. N. Houk, R. M. Franzini. Angew. Chem. Int. Engl. Ed., 2019, 58, 9043-9048. [Article]
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"A Focused DNA-encoded Chemical Library for the Discovery of Inhibitors of NAD+-dependent enzymes" L. H. Yuen, S. Dana, Y. Liu , S. I. Bloom, A. G. Thorsell, D. Neri, A. J. Donato, D. B. Kireev, H. Schuler, R. M. Franzini. J. Am. Chem. Soc., 2019, 141, 5169-5181. [Article]
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"Dissociative Bioorthogonal Reactions" J. Tu, M. Xu, R. M. Franzini. ChemBioChem, 2019, 20, 1615-1627. [Article]
2018
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"Bioorthogonal Removal of 3-Isocyanopropyl Groups Enables the Controlled Release of Fluorophores and Drugs in Vivo" J. Tu, M. Xu, S. Parvez, R. T. Peterson, R. M. Franzini. J. Am. Chem. Soc. 2018, 140, 8410-8414. [Article]
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"A DNA‐Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition" N. Favalli, S. Biendl, M. Hartmann, J. Piazzi, F. Sladojevich, S. Graslund, P. J. Brown, K. Nareoja, H. Schuler, J. Scheuermann, R. Franzini, D. Neri. ChemMedChem 2018, 13, 1303-1307. [Article]
2017
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"Dissociative reactions of benzonorbornadienes with tetrazines: scope of leaving groups and mechanistic insights" M. Xu, R. Galindo-Murillo, T. Cheatham, R. M. Franzini. Org. Biomol. Chem. 2017, 15, 9855-9865. [Article]
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"Rapid and efficient tetrazine-induced drug release from highly stable benzonorbornadiene derivatives" M. Xu, J. Tu, R. M. Franzini. Chem. Commun. 2017, 53, 6271-6274. [Article]
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"Stability of Oligonucleotide–Small Molecule Conjugates to DNA-Deprotection Conditions" L. H. Yuen, R. M. Franzini. Bioconjugate Chem. 2017, 28, 1076-1083.
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"Achievements, Challenges, and Opportunities in DNA‐Encoded Library Research: An Academic Point of View" L. H. Yuen, R. M. Franzini. ChemBioChem 2017, 18, 829-836.
2016
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"Chemical Space of DNA-Encoded Libraries" R. M. Franzini, C. Randolph. J. Med. Chem. 2016, 59, 6629-6644. [Article]
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"Automated screening for small organic ligands using DNA-encoded chemical libraries" W. Decurtins, M. Wichert, R. M. Franzini, F. Buller, M. A. Stravs, Y. Zhang, D. Neri, J. Scheuermann. Nat. Protocols, 2016, 11, 764-780.