About

Dirk Trauner, PhD, is the George A. Weiss University Professor in the Department of Systems Pharmacology and Translational Therapeutics at the Perelman School of Medicine, University of Pennsylvania. He completed his PhD at the University of Vienna, Austria, in 1997. His research focuses on the development and application of photopharmacology, particularly the optical control of biological processes using photoswitchable compounds. Trauner's work includes the synthesis of natural products, the design of photoswitchable lipids, and the development of tools for controlling cell signaling and membrane dynamics with light. He has made significant contributions to understanding how photoswitchable molecules affect lipid bilayers and embedded proteins, enabling precise manipulation of cellular functions. His research group advances the field of optical control in biological systems, contributing to both fundamental science and potential therapeutic applications.

Research topics

• Biochemistry
• Microbiology
• Chemistry
• Biology

Selected publications

• Correction to “Synthesis of Collinoketones via Biomimetic [6 + 4] Cycloaddition”

  Journal of the American Chemical Society · 2026-01-05

  articleSenior authorCorresponding
  PublisherDOI

• Total Synthesis of the Diterpene Alkaloid Thelepogine Through Enyne Hydroamination

  ChemRxiv · 2026-05-07

  articleOpen accessSenior author

  The total synthesis of the atypical diterpene alkaloid thelepogine is reported. Our pathway features the asymmetric construction of a carbotricyclic intermediate that undergoes a 2,3-Wittig–Still rearrangement of a tetrasubstituted allylic alcohol, installing two adjacent quaternary stereocenters. The α-tertiary amine of thelepogine was delineated from a quaternary carbon through a Beckmann-type rearrangement, while the unusual pyrrolizidine moiety was assembled through a copper(I)-catalyzed (4+1) cycloaddition of an amino enyne, amounting to a twofold hydroamination. Our synthesis enabled the full spectroscopic characterization of thelepogine, which had previously been characterized only by single-crystal X-ray diffraction of a derivative, and opens the door to comprehensive biological evaluation.

  PublisherDOI

• Photocontrolled trimethoprim PROTACs targeting the eDHFR protein tag

  Nature Communications · 2025-12-27 · 2 citations

  articleOpen access

  Proteolysis targeting chimeric small molecules (PROTACs) offer a strategy for degrading disease-associated proteins or controlling engineered protein tags fused to therapeutic proteins, like chimeric antigen receptors (CARs). New approaches are needed that allow spatiotemporal control of PROTAC activity, restricting degrader activity to targeted cells. Photopharmacology offers a solution by enabling light-mediated spatial control of drug action. Here, we synthesize photocaged and photoswitchable PROTAC molecules and test their regulation of proteins tagged with E. coli dihydrofolate reductase (eDHFR) in tumor and CAR-T cells. Several of the molecules are derived from triazole-linked trimethoprim-PROTACs (TMP-TACtz), that degrade eDHFR fused proteins at picomolar concentrations, show degradation in cells with low cereblon E3 ligase levels, and have little off-target effects. The photocleavable compound, TMP-TAC-PC yields the best light-mediated regulation of CAR T cell cytotoxicity and cytokine secretion. This work introduces photocontrolled, tag-directed degraders for controlling protein expression in tumor cells and CAR T cells. In this work authors demonstrate how photocontrolled tag-targeted degradation enables precise, spatiotemporal control of protein expression in tumor cells and CAR T cells, offering an esapproach for regulating engineered proteins with light.

  PublisherDOI

• Die Chemie und Biologie der Tetrodotoxin Naturstofffamilie

  Angewandte Chemie · 2025-06-18

  articleOpen access

  Zusammenfassung Tetrodotoxin ist ein neurotoxisches Meeresalkaloid, das erstmals 1909 aus Kugelfischen isoliert und nach der biologischen Ordnung der Tetraodontiformes benannt wurde. Seit seiner Strukturaufklärung im Jahr 1964 hat es aufgrund seiner außergewöhnlichen Polarität, seiner komplexen Struktur und seiner bedeutenden biologischen Aktivität das Interesse synthetischer organischer Chemiker auf sich gezogen. In dieser Übersichtsarbeit wird die Vielfalt der Tetrodotoxin Naturstofffamilie hervorgehoben und die Herkunft der Derivate, biosynthetische Hypothesen und biologische Aktivitäten erörtert. Darüber hinaus werden potenzielle therapeutische Anwendungen und Studien zur Struktur‐Aktivitäts Beziehung sowie die bisher veröffentlichten Totalsynthesen des Naturstoffs und ausgewählter Derivate behandelt.

  PublisherDOI

• Reversible Antagonism of Dopamine D1 Receptor using a Photoswitchable Remotely Tethered Ligand

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-15

  preprintOpen accessSenior authorCorresponding

  Dopamine D1 receptor (D1R) plays key roles in health and disease. D1R is broadly expressed throughout the brain and body and is dynamically activated in response to endogenous dopamine, making it difficult to target this receptor with sufficient precision. We previously developed a robust light-activatable, tetherable agonist for D1R, wherein a temporally precise photo-switch (the P compound) binds to a genetically-encoded membrane anchoring protein (the M protein) in specific brain locations and cell types. Here we extended our approach by developing a complementary antagonist P compound that could be used to block specific populations of D1R in the brain with precise timing. Together, we have generated a robust toolkit for interrogating D1R function in the brain with unprecedented precision.

  PublisherOA PDFDOI

• Synthesis of Collinoketones via Biomimetic [6+4] Cycloaddition

  ChemRxiv · 2025-09-02

  articleOpen accessSenior author

  Cycloadditions are among the most powerful reactions for constructing molecular complexity. The archetypal example is the [4+2] (Diels–Alder) cycloaddition, which efficiently furnishes cyclohexene derivatives. In comparison, the [6+4] cycloaddition, which forms cyclodecatriene derivatives from triene and diene reactants, is far less common. Here, we report a short and stereoselective synthesis of a highly unsaturated macrolactone that has been proposed as a biosynthetic precursor of the tricyclic cyclodecatriene collinoketone A and the neuroprotective natural product collinolactone. We find that this macrolactone undergoes effective transannular [6+4] cycloaddi-tions to afford stereoisomers of collinoketone A, which we name collinoketones B and C. Our work reassigns the structure of the natural product reported as collinoketone A and highlights the complexity of [6+4] cycloadditions with conformationally flexible substrates.

  PublisherOA PDFDOI

• Bidirectional optical control of osteogenesis with a light activated vitamin D mimetic

  ChemRxiv · 2025-12-14

  article

  The secosteroid vitamin D is essential for human health maintaining bone metabolism, calcium homeostasis and immune function via the vitamin D receptor (VDR). VDR activation has complex and cell-specific effects in multiple tissues and spatial control of VDR activity is desirable. Here we developed vitD mimetics bearing a photo-switchable azobenzene motif to achieve spatiotemporal resolution in VDR activation. Structure-guided tuning of regiochemistry and H-bonding motifs provided a potent and selective vitD mimetic that can be reversibly switched in cellulo between agonist and antagonist states with light. In a model of osteogenesis, this precision tool mediated light-dependent osteogenic and osteolytic effects corroborating bidirectional optical control of VDR activity.

  PublisherDOI

• Photolipid Isomerization in Multicomponent Lipid Membranes: Effects of Temperature and Charge

  Langmuir · 2025-08-20

  article

  Photoswitchable lipids based on azobenzene offer efficient optical control over membrane properties, making them advanced molecular nanoagents for biomedical applications. However, many details regarding their photoswitching dynamics in complex lipid environments or under physiological temperatures are still poorly understood. Here, we investigate how temperature and membrane charge affect the mixing and photoswitching efficiency of the photolipid azo-PC in membrane assemblies. In giant unilamellar vesicles (GUVs), the presence of charge lowers the mixing temperature, while small liposomes reveal a striking temperature dependence in photoswitching dynamics and efficiency. These findings show that temperature plays a critical role in enabling more complete switching in lipid mixtures, underscoring the need to account for thermal effects and charge in lipid systems for biomedical applications.

  PublisherDOI

• Photoswitchable phospholipids for the optical control of membrane processes, protein function, and drug delivery

  Communications Materials · 2025-04-01 · 15 citations

  reviewOpen accessSenior author

  Recent insights into the function and composition of cell membranes have transformed our understanding from primarily viewing these structures as passive barriers to recognizing them as dynamic entities actively involved in many cellular functions. This review highlights advances in the photopharmacology of phospholipids, emphasizing in particular the role of diacylglycerophospholipids and the impact of their polymorphic nature on synthetic and cellular membrane properties and metabolic processes. We explore photoswitchable diacylglycerophospholipids, termed ‘photolipids’, which permit precise, reversible modifications of membrane properties via light-induced isomerization. The ability to optically switch phospholipid properties has potential applications in controlling membrane dynamics, protein function, and cellular signaling pathways, and offers promising strategies for drug delivery and treatment of diseases. Developments in azobenzene and hemithioindigo based photolipids are discussed, underscoring their utility in biomedical and biomaterial science applications due to their unique photophysical properties. Cell membranes are dynamic entities that are actively involved in many cellular processes. This Review highlights recent advances in the photopharmacology of phospholipids, exploring the photoswitchable properties of membranes and how they are used in biomedical and biomaterial science applications.

  PublisherOA PDFDOI

• Development of Photoswitchable Cholesterol Derivatives through Side Chain Replacement

  Journal of the American Chemical Society · 2025-11-12

  articleSenior authorCorresponding

  Cholesterol is ubiquitous in biology, shaping membrane properties and serving as a biosynthetic precursor for essential signaling molecules and hormones─and, in some contexts, acting as a signaling molecule itself. Here, we describe the development of photoswitchable versions of cholesterol that retain the lipophilic profile of the parent compound. These analogs were designed through computationally guided replacement of the native iso-octyl side chain with azobenzene-based photoswitches. Our compounds, termed photocholesterols (PChols), were assembled through a modular and readily diversifiable semisynthetic route involving transition metal-catalyzed cross-couplings followed by stereo- and chemoselective hydrogenations. They can be used to optically control binding to the sterol transport proteins ORP1/2 and OSBP, which play key roles in distributing cholesterol within intracellular compartments. Our work establishes a template for photoresponsive sterols that closely mimic cholesterol and may be applied broadly to investigate cholesterol’s roles in membrane behavior, signaling, and transport.

  PublisherDOI

Recent grants

• NIH Grant R01GM067636

  NIH · $1.2M · 2008

• Optical control of neuromodulatory GPCRs

  NIH · $3.3M · 2020–2024

• Synthetic Studies on Alkaloids Isolated from Lycopodium annotium and a New Synthesis of Tetrodotoxin

  NSF · $484k · 2019–2022

• CAREER: Pericyclic Reaction Cascades in the Synthesis of Complex Molecules

  NSF · $580k · 2004–2008

• Exploring Synthetic Ligands for Potassium Channels

  NSF · $402k · 2007–2010

Frequent coauthors

• Johannes Broichhagen

  Leibniz-Forschungsinstitut für Molekulare Pharmakologie

  165 shared

• Péter Mayer

  LMU Klinikum

  131 shared

• Ehud Y. Isacoff

  107 shared

• Philipp Leippe

  Max Planck Institute for Medical Research

  106 shared

• Johannes Morstein

  University of California, San Francisco

  96 shared

• James A. Frank

  Oregon Health & Science University

  95 shared

• David J. Hodson

  Churchill Hospital

  78 shared

• Bryan S. Matsuura

  68 shared

Labs

• Trauner Research GroupPI

Education

• Dr. rer. nat. (Ph.D.), Chemistry

  University of Vienna

  1997

• Graduate Student, Chemistry

  Goethe University Frankfurt

  1996

• Diplomchemiker, Chemistry

  Freie Universität Berlin

  1995

Awards & honors

• George A. Weiss University Professor