Publications by authors named "Patrick Altermatt"

4 Publications

  • Page 1 of 1

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

Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia.

J Clin Invest 2019 12 9;130(1):491-506. Epub 2019 Dec 9.

β-Thalassemia is a genetic anemia caused by partial or complete loss of β-globin synthesis, leading to ineffective erythropoiesis and RBCs with a short life span. Currently, there is no efficacious oral medication modifying anemia for patients with β-thalassemia. The inappropriately low levels of the iron regulatory hormone hepcidin enable excessive iron absorption by ferroportin, the unique cellular iron exporter in mammals, leading to organ iron overload and associated morbidities. Correction of unbalanced iron absorption and recycling by induction of hepcidin synthesis or treatment with hepcidin mimetics ameliorates β-thalassemia. However, hepcidin modulation or replacement strategies currently in clinical development all require parenteral drug administration. We identified oral ferroportin inhibitors by screening a library of small molecular weight compounds for modulators of ferroportin internalization. Restricting iron availability by VIT-2763, the first clinical stage oral ferroportin inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia intermedia. VIT-2763 not only improved erythropoiesis but also corrected the proportions of myeloid precursors in spleens of Hbbth3/+ mice. VIT-2763 is currently being developed as an oral drug targeting ferroportin for the treatment of β-thalassemia.
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http://dx.doi.org/10.1172/JCI129382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934209PMC
December 2019

Functional characterization of fluorescent hepcidin.

Bioconjug Chem 2013 Sep 14;24(9):1527-32. Epub 2013 Aug 14.

Chemical Biology Group, Institute of Pharmaceutical Sciences, and ‡Nutrition and Diabetes Research Group, King's College London , Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, U.K.

Hepcidin is a peptide hormone that regulates homeostasis in iron metabolism. It binds to the sole known cellular iron exporter ferroportin (Fpn), triggers its internalization, and thereby modulates the efflux of iron from cells. This functional property has been adopted in this study to assess the bioactivity and potency of a range of novel fluorescent hepcidin analogues. Hepcidin was selectively labeled with 6-carboxyfluorescein (CF) and 6-carboxytetramethylrhodamine (TMR) using Fmoc solid phase peptide chemistry. Internalization of Fpn by hepcidin was assessed by high-content microscopic analysis. Both K18- and M21K-labeled hepcidin with TMR and CF exhibited measurable potency when tested in cultured MDCK and T47D cells expressing human ferroportin. The bioactivity of the labeled hepcidin varies with the type of fluorophore and site of attachment of the fluorophores on the hepcidin molecule.
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http://dx.doi.org/10.1021/bc400121xDOI Listing
September 2013

Identification of the rapamycin-sensitive phosphorylation sites within the Ser/Thr-rich domain of the yeast Npr1 protein kinase.

Rapid Commun Mass Spectrom 2008 Dec;22(23):3743-53

Department of Biochemistry, Biozentrum of the University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.

The Saccharomyces cerevisae nitrogen permease reactivator Npr1 is a hyperphosphorylated protein that belongs to a fungus-specific family of Ser/Thr protein kinases dedicated to the regulation of plasma membrane transporters. Its activity is regulated by the TOR (target of rapamycin) signalling pathway. Inhibition of the TOR proteins by treating yeast cells with the immunosuppressant drug rapamycin promotes rapid dephosphorylation of Npr1. To identify the rapamycin-sensitive phosphorylation sites in yeast Npr1, glutathione-S-transferase (GST)-tagged Npr1 was isolated from untreated or rapamycin-treated cells, and analyzed by mass spectrometry. Here, we report for the first time 22 phosphorylation sites that are clustered in two regions of the N-terminal serine-rich domain. All phosphorylation sites, except two, were found to be rapamycin-sensitive. Some phosphorylation sites are contained in motifs that closely resemble those in mammalian S6K (serines followed by a tyrosine or a phenylalanine) and 4E-BP1 (serines followed by a proline). Other sites, such as serines followed by Ala, Asn, Gln, His, Ile, Leu, or Val, appear to define new motifs. Thus, TOR controls an unusually broad array of phosphorylation sites in Npr1. In addition to phosphorylation by upstream kinases, Npr1 undergoes autophosphorylation that was mapped to three distinct serines in the N-terminal domain of which Ser257 appears to be the main autophosphorylation site. Site-directed mutagenesis confirmed the mass spectral assignments of the autophosphorylation sites and shows that Ser257 is specifically involved in forming an in vitro substrate-binding site.
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http://dx.doi.org/10.1002/rcm.3790DOI Listing
December 2008