Publications by authors named "Philipp Leippe"

11 Publications

  • Page 1 of 1

Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ).

J Med Chem 2020 10 21;63(19):10908-10920. Epub 2020 Sep 21.

Department of Chemistry, New York University, New York, New York 10003, United States.

Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome proliferator-activated receptor γ (PPARγ). Based on known PPARγ ligands (MDG548, GW1929, and rosiglitazone), we have designed and synthesized azobenzene derivatives, termed and , which were confirmed to be active in cell-based assays. Subsequent computer-aided optimization of resulted in the photohormone , which bound and activated PPARγ preferentially in its light-activated -configuration.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00654DOI Listing
October 2020

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

Transformation of Receptor Tyrosine Kinases into Glutamate Receptors and Photoreceptors.

Angew Chem Int Ed Engl 2020 04 4;59(17):6720-6723. Epub 2020 Mar 4.

Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille (CIIL), 59000, Lille, France.

Receptor tyrosine kinases (RTKs) are key regulators of cellular functions in metazoans. In vertebrates, RTKs are mostly activated by polypeptides but are not naturally sensitive to amino acids or light. Taking inspiration from Venus kinase receptors (VKRs), an atypical family of RTKs found in nature, we have transformed the human insulin (hIR) and hepatocyte growth factor receptor (hMET) into glutamate receptors by replacing their extracellular binding domains with the ligand-binding domain of metabotropic glutamate receptor type 2 (mGluR2). We then imparted light sensitivity through covalent attachment of a synthetic glutamate-based photoswitch via a self-labelling SNAP tag. By employing a Xenopus laevis oocyte kinase activity assay, we demonstrate how these chimeric RTKs, termed light-controlled human insulin receptor (LihIR) and light-controlled human MET receptor (LihMET), can be used to exert optical control over the insulin or MET signaling pathways. Our results outline a potentially general strategy to convert RTKs into photoreceptors.
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http://dx.doi.org/10.1002/anie.201915352DOI Listing
April 2020

Oxidative Approach Enables Efficient Access to Cyclic Azobenzenes.

J Am Chem Soc 2019 10 17;141(43):17295-17304. Epub 2019 Oct 17.

Department of Chemistry and Center for Integrated Protein Science (CIPSM) , Ludwig Maximilian University Munich , 81377 Munich , Germany.

Azobenzenes are versatile photoswitches that have found widespread use in a variety of fields, ranging from photopharmacology to the material sciences. In addition to regular azobenzenes, the cyclic diazocines have recently emerged. Although diazocines have fascinating conformational and photophysical properties, their use has been limited by their synthetic accessibility. Herein, we present a general, high-yielding protocol that relies on the oxidative cyclization of dianilines. In combination with a modular substrate synthesis, it allows for rapid access to diversely functionalized diazocines on gram scales. Our work systematically explores substituent effects on the photoisomerization and thermal relaxation of diazocines. It will enable their incorporation into a wide variety of functional molecules, unlocking the full potential of these emerging photoswitches. The method can be applied to the synthesis of a new cyclic azobenzene with a nine-membered central ring and distinct properties.
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http://dx.doi.org/10.1021/jacs.9b08794DOI Listing
October 2019

Designing azobenzene-based tools for controlling neurotransmission.

Curr Opin Struct Biol 2019 08 28;57:23-30. Epub 2019 Feb 28.

The Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Electronic address:

Chemical and electrical signaling at the synapse is a dynamic process that is crucial to neurotransmission and pathology. Traditional pharmacotherapy has found countless applications in both academic labs and the clinic; however, diffusible drugs lack spatial and temporal precision when employed in heterogeneous tissues such as the brain. In the field of photopharmacology, chemical attachment of a synthetic photoswitch to a bioactive ligand allows cellular signaling to be controlled with light. Azobenzenes have remained the go-to photoswitch for biological applications due to their tunable photophysical properties, and can be leveraged to achieve reversible optical control of numerous receptors and ion channels. Here, we discuss the most recent advances in photopharmacology which will improve the use of azobenzene-based probes for neuroscience applications.
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http://dx.doi.org/10.1016/j.sbi.2019.01.022DOI Listing
August 2019

Optical Control of a Delayed Rectifier and a Two-Pore Potassium Channel with a Photoswitchable Bupivacaine.

ACS Chem Neurosci 2018 12 14;9(12):2886-2891. Epub 2018 Aug 14.

Department of Chemistry and Center for Integrated Protein Science , LMU Munich , Butenandtstr. 5-13 , 81377 Munich , Germany.

Photoswitchable blockers of potassium channels can be used to optically control neuronal excitability and hold great promise for vision restoration. Here, we report a series of improved photoswitchable blockers that are furnished with a new pharmacophore based on the local anesthetic bupivacaine. These azobupivacaines (ABs) enable optical control over the delayed rectifier channel K2.1. and target the two-pore domain potassium channel TREK-1. For the first time, we have identified a compound that blocks conductance in the dark and potentiates it upon illumination. Using light as a trigger, ABs efficiently and reversibly silence action potential firing of hippocampal neurons in acute mouse brain slices.
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http://dx.doi.org/10.1021/acschemneuro.8b00279DOI Listing
December 2018

Conditional and Reversible Activation of Class A and B G Protein-Coupled Receptors Using Tethered Pharmacology.

ACS Cent Sci 2018 Feb 16;4(2):166-179. Epub 2018 Jan 16.

Institute of Metabolism and Systems Research (IMSR), University of Birmingham, B15 2TT, Birmingham, United Kingdom.

Understanding the activation and internalization of G protein-coupled receptors (GPCRs) using conditional approaches is paramount to developing new therapeutic strategies. Here, we describe the design, synthesis, and testing of , a benzylguanine-linked peptide agonist of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR required for maintenance of glucose levels in humans. covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged cAMP generation, Ca rises, and intracellular retention of the receptor. These effects were readily switched OFF following cleavage of the introduced disulfide bridge using the cell-permeable reducing agent -mercaptoethanol (BME). A similar approach could be extended to a class A GPCR using , a benzylguanine-linked peptide agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), which is involved in food intake and growth. Thus, and allow SNAP-tag-directed activation of class A and B GPCRs involved in gut hormone signaling in a reversible manner. This tactic, termed reductively cleavable agONist (RECON), may be useful for understanding GLP-1R and GHS-R1a function both and , with applicability across GPCRs.
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http://dx.doi.org/10.1021/acscentsci.7b00237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832994PMC
February 2018

Synthesis of Photoswitchable Δ-Tetrahydrocannabinol Derivatives Enables Optical Control of Cannabinoid Receptor 1 Signaling.

J Am Chem Soc 2017 12 12;139(50):18206-18212. Epub 2017 Dec 12.

Department of Chemistry and Center for Integrated Protein Science, Ludwig Maximilians University Munich , Butenandtstraße 5-13, 81377 Munich, Germany.

The cannabinoid receptor 1 (CB1) is an inhibitory G protein-coupled receptor abundantly expressed in the central nervous system. It has rich pharmacology and largely accounts for the recreational use of cannabis. We describe efficient asymmetric syntheses of four photoswitchable Δ-tetrahydrocannabinol derivatives (azo-THCs) from a central building block 3-Br-THC. Using electrophysiology and a FRET-based cAMP assay, two compounds are identified as potent CB1 agonists that change their effect upon illumination. As such, azo-THCs enable CB1-mediated optical control of inwardly rectifying potassium channels, as well as adenylyl cyclase.
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http://dx.doi.org/10.1021/jacs.7b06456DOI Listing
December 2017

Specificity and Speed: Tethered Photopharmacology.

Biochemistry 2017 10 14;56(39):5214-5220. Epub 2017 Sep 14.

Department of Chemistry and Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München , Butenandtstrasse 5-13, 81377 Munich, Germany.

Genetics and pharmacology are often seen as two distinct approaches to interrogating, elucidating, and manipulating biological systems. The former is renowned for its precision whereas the latter for its fast kinetics, reversibility, and practicality. Here, we show that both can be joined as "tethered pharmacology", wherein a genetically programmed bioconjugation site provides selectivity and a tethered pharmacophore provides function. The speed of onset, and especially cessation, of pharmacological activity can be greatly enhanced by incorporating photoswitches and using light as the trigger ("tethered photopharmacology"). Genetically encoded, tethered photopharmacology is a variant of optogenetics and could even play a role in medicine wherever gene therapy is viable. However, gene therapy may not be necessary if sufficiently selective tethering strategies that operate on wild-type receptors can be developed.
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http://dx.doi.org/10.1021/acs.biochem.7b00687DOI Listing
October 2017

Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors.

Proc Natl Acad Sci U S A 2017 04 10;114(17):E3546-E3554. Epub 2017 Apr 10.

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720;

G protein-coupled receptor (GPCR) signaling occurs in complex spatiotemporal patterns that are difficult to probe using standard pharmacological and genetic approaches. A powerful approach for dissecting GPCRs is to use light-controlled pharmacological agents that are tethered covalently and specifically to genetically engineered receptors. However, deficits in our understanding of the mechanism of such photoswitches have limited application of this approach and its extension to other GPCRs. In this study, we have harnessed the power of bioorthogonal tethering to SNAP and CLIP protein tags to create a family of light-gated metabotropic glutamate receptors (mGluRs). We define the mechanistic determinants of photoswitch efficacy, including labeling efficiency, dependence on photoswitch structure, length dependence of the linker between the protein tag and the glutamate ligand, effective local concentration of the glutamate moiety, and affinity of the receptor for the ligand. We improve the scheme for photoswitch synthesis as well as photoswitch efficiency, and generate seven light-gated group II/III mGluRs, including variants of mGluR2, 3, 6, 7, and 8. Members of this family of light-controlled receptors can be used singly or in specifically labeled, independently light-controlled pairs for multiplexed control of receptor populations.
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http://dx.doi.org/10.1073/pnas.1619652114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410775PMC
April 2017

Orthogonal Optical Control of a G Protein-Coupled Receptor with a SNAP-Tethered Photochromic Ligand.

ACS Cent Sci 2015 Oct 16;1(7):383-93. Epub 2015 Oct 16.

Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany; Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.

The covalent attachment of synthetic photoswitches is a general approach to impart light sensitivity onto native receptors. It mimics the logic of natural photoreceptors and significantly expands the reach of optogenetics. Here we describe a novel photoswitch design-the photoswitchable orthogonal remotely tethered ligand (PORTL)-that combines the genetically encoded SNAP-tag with photochromic ligands connected to a benzylguanine via a long flexible linker. We use the method to convert the G protein-coupled receptor mGluR2, a metabotropic glutamate receptor, into a photoreceptor (SNAG-mGluR2) that provides efficient optical control over the neuronal functions of mGluR2: presynaptic inhibition and control of excitability. The PORTL approach enables multiplexed optical control of different native receptors using distinct bioconjugation methods. It should be broadly applicable since SNAP-tags have proven to be reliable, many SNAP-tagged receptors are already available, and photochromic ligands on a long leash are readily designed and synthesized.
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http://dx.doi.org/10.1021/acscentsci.5b00260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827557PMC
October 2015