Daniel Grell

University of Lausanne

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Gabriele Tuchscherer

Institute of Polymers

Patricia Durieux

Syngenta (Switzerland)

Manfred Mutter

Debiopharm (Switzerland)

Christian Kardinal

Medizinische Hochschule Hannover

Jimena Fernández‐Carneado

Association for Innovation and Biomedical Research on Light and Image

Yoshiro Tatsu

National Institute of Advanced Industrial Science and Technology

J Hauert

University Hospital of Lausanne

Stephan M. Feller

Martin Luther University Halle-Wittenberg

Tibor Kovacsovics

City of Hope

Jane S. Richardson

Duke University

Cooperative Institutions

University of Lausanne

University Hospital of Lausanne

École Polytechnique Fédérale de Lausanne

University of Basel

University of Geneva

Hôpital Orthopédique de la Suisse Romande

Centre National de la Recherche Scientifique

Universitat de Barcelona

Inserm

Novartis (Switzerland)

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Der molekularen Erkennung auf der Spur: die duale Funktion von Pseudoprolinen für das Design von SH3-Liganden

Angewandte Chemie (2001)

Gabriele Tuchscherer Daniel Grell Yoshiro Tatsu Patricia Durieux Jimena Fernández‐Carneado

Pseudoproline (ΨPro) dienen als vielseitige Bausteine, die in der Lage sind, die bioaktive Konformation eines Peptidliganden sowie die für eine Protein-Protein-Wechselwirkung komplementäre Oberflächenstruktur zu induzieren. Diese duale Funktion von ΨPro wurde an prolinreichen Peptiden als effizienten Liganden für SH3-Domänen aufgezeigt (siehe Bild).

10.1002/1521-3757(20010803)113:15<2930::aid-ange2930>3.0.co;2-2

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Protein design and folding: template trapping of self‐assembled helical bundles

Journal of Peptide Science (2001)

Daniel Grell Jane S. Richardson Manfred Mutter

An experimental system is described, permitting a detailed and systematic analysis of the factors governing self-assembly of amphipathic helices, e.g. to a four-helical bundle, a subject of major relevance for tertiary structure formation, protein folding and design. Following the Template Assembled Synthetic Proteins (TASP) approach, helices of different packing potential are competitively assembled in solution with a preformed two-helix TASP molecule, and after equilibration are covalently attached ('template trapping') via chemoselective thioether formation. The quantitative analysis of the individual TASP molecules by high performance liquid chromatography (HPLC) and electrospray mass spectrometry (ES-MS) allows the delineation of the role of complementary packing in helix bundle formation. The procedure established represents a general tool for the experimental verification of modern concepts in molecular recognition.

Helix bundle

Folding (DSP implementation)

Protein design

Helix (gastropod)

10.1002/psc.308

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Citations (14)

Design and synthesis of vWF TASP, a novel synthetic peptide mimicking the A1 domain of the von Willebrand factor

Blood (2001)

Tibor Kovacsovics Sophie Mathieu A. Fernandez-Carneado Daniel Grell Matthieu Schapira

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Assembly of binding loops on aromatic templates as VCAM-1 mimetics

Journal of Peptide Science (1999)

Francesco Peri Daniel Grell Pascal Dumy Yoshihiro Yokokawa Karl Welzenbach

The design and synthesis of cyclic mimetics of VCAM-1 protein that reproduce the integrin-binding domain are presented. The unprotected peptide precursor 37–43, Thr-Gln-Ile-Asp-Ser-Pro-Leu, was grafted onto functional templates of type naphthalene, biphenyl and benzyl through the chemoselective formation of C- and N-terminal oximes resulting in a mixture of four isomeric forms due to syn–anti isomerism of the oxime bonds. Some isomers could be monitored by HPLC and identified by NMR. The molecule containing a naphthalene-derived template was found to inhibit the VCAM-1/VLA-4 interaction more efficiently than previously reported for sulfur-bridged cyclic peptides containing similar sequences. The finding confirms the importance of incorporating conformational constraints between the terminal ends of the peptide loop 37–43 in the design of synthetic inhibitors of the VCAM-1/integrin interaction. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.

VCAM-1

Biphenyl

Template

Cyclic peptide

10.1002/(sici)1099-1387(199907)5:7<313::aid-psc200>3.0.co;2-f

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Citations (6)

Extending the concept of template‐assembled synthetic proteins

Journal of Peptide Research (1999)

Gabriele Tuchscherer Daniel Grell M. Mathieu M. Mutter

Abstract: The creation of native‐like macromolecules in copying nature’s way represents a fascinating challenge in protein chemistry today. In the absence of a detailed knowledge of the complex folding pathway the ultimate goal in protein de novo design, the construction of artificial proteins with predetermined three‐dimensional structure and tailor‐made functions based on a defined, generally valid set of rules, appears to be still out of reach. With progress in synthesis strategies and biostructural characterization methods, topological templates have become a versatile tool for inducing and stabilizing secondary and tertiary structures, such as protein loops, β‐turns, α‐helices, β‐sheets and a variety of folding motifs. In this article, we extend the concept of template‐assembled synthetic proteins for the construction of protein‐like topologies with multiply bridged, oligocyclic chain architectures termed locked‐in tertiary folds that exhibit unique physicochemical and folding properties because of the highly confined conformational space. Furthermore, we show that some fundamental questions in protein assembly can be approached applying the template concept. Using covalent template trapping of self‐associated peptide assemblies in aqueous solution the structural and physical forces guiding protein folding, supramolecular assembly and molecular recognition processes can be studied on a molecular level.

Template

Folding (DSP implementation)

Foldamer

Structural motif

Protein design

Molecular Recognition

Synthetic Biology

Copying

10.1034/j.1399-3011.1999.00120.x

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Citations (46)

Targeting Molecular Recognition: Exploring the Dual Role of Functional Pseudoprolines in the Design of SH3 Ligands

Angewandte Chemie International Edition (2001)

Gabriele Tuchscherer Daniel Grell Yoshiro Tatsu Patricia Durieux Jimena Fernández‐Carneado

Pseudoprolines (ΨPro) have been developed as tools for inducing bioactive conformations that allow for optimal spatial complementation in protein–protein interactions. This dual function of ΨPro was explored for tuning proline-rich peptides as potent ligands for SH3 domains (see picture).

10.1002/1521-3773(20010803)40:15<2844::aid-anie2844>3.0.co;2-f

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Citations (15)

The dual role of functional pseudo-prolines for the design of novel SH3 ligands

Daniel Grell Yoshiro Tatsu Patricia Durieux Jimena Fernandez Christian Kardinal

Pseudo-proline building blocks exert a dual functionality in enhancing and stabilizing the relevant polyproline II (PPII) conformation and increasing and optimizing van der Waals contacts and hydrogen bonding to the receptor mols. thus modifying affinity and specificity. They are highly useful in studying ligand recognition mediated by Src homol. 3 domains essential in cellular regulation and protein-protein interactions. The 2-C substituents promote the induction of the required PPII helix and allow for optimal complementation of the SH3 topog. [on SciFinder (R)]

Polyproline helix

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Assembly of binding loops on aromatic templates as VCAM-1 mimetics

Journal of Peptide Science (1999)

Francesco Peri Daniel Grell Pascal Dumy Yoshihiro Yokokawa Karl Welzenbach

VCAM-1

Template

Biphenyl

Cyclic peptide

10.1002/(sici)1099-1387(199907)5:7<313::aid-psc200>3.3.co;2-6

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A Template‐Assembled Synthetic Protein Surface Mimetic of the von Willebrand Factor A1 domain Inhibits Botrocetin‐Induced Platelet Aggregation

ChemBioChem (2004)

J Hauert Jimena Fernández‐Carneado Olivier Michielin Stéphane Mathieu Daniel Grell

Abstract Platelet adhesion, the initial step of platelet activation, is mediated by the interaction of von Willebrand factor (VWF) with its platelet receptor, the GPIb–IX complex. The binding of VWF to GPIb–IX is induced either by increased shear stress or by exogenous modulators, such as botrocetin. At a molecular level, this interaction takes place between the A1 domain of VWF and the GPIbα chain of the GPIb–IX complex. We report here the design and functional characteristics of a VWF template‐assembled synthetic protein (TASP), a chimeric four‐helix‐bundle TASP scaffold mimicking the surface of the A1 domain. Twelve residues located on helices α3 and α4 in the native A1 domain were grafted onto a surface formed by two neighboring helices of the TASP. VWF TASP was found to inhibit specifically botrocetin‐induced platelet aggregation and to bind both botrocetin and GPIbα. However, in contrast to the native A1 domain, VWF TASP did not bind simultaneously to both ligands. Modeling studies revealed that the relative orientation of the α helices in VWF TASP led to a clash of bound botrocetin and GPIbα. These results demonstrate that a chimeric four‐helix‐bundle TASP as a scaffold offers a suitable surface for presenting crucial residues of the VWF A1 domain; the potential of the TASP approach for de novo protein design and mimicry is thereby illustrated.

Glycoprotein Ib

Helix (gastropod)

10.1002/cbic.200300826

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Citations (17)

Surface grafting onto template‐assembled synthetic protein scaffolds in molecular recognition

Biopolymers (2000)

Jimena Fernandez‐ Carneado Daniel Grell Patricia Durieux J Hauert Tibor Kovacsovics

Creating functional biological molecules de novo requires a detailed understanding of the intimate relationship between primary sequence, folding mechanism, and packing topology, and remains up to now a most challenging goal in protein design and mimicry. As a consequence, the use of well-defined robust macromolecules as scaffolds for the introduction of function by grafting surface residues has become a major objective in protein engineering and de novo design. In this article, the concept of scaffolds is demonstrated on some selected examples, illustrating that novel types of functional molecules can be generated. Reengineered proteins and, most notably, de novo designed peptide scaffolds exhibiting molecular function, are ideal tools for structure–function studies and as leads in drug design. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 55: 451–458, 2000

Folding (DSP implementation)

Protein design

Sequence (biology)

Protein Engineering

Molecular mimicry

10.1002/1097-0282(2000)55:6<451::aid-bip1020>3.3.co;2-t

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