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Jochen Spiegel Philipp M. Cromm Prof. Dr. Aymelt Itzen Prof. Dr. Roger S. Goody Dr. Tom N. Grossmann Prof. Dr. Herbert Waldmann 《Angewandte Chemie (International ed. in English)》2014,53(9):2498-2503
Small GTPases are molecular switches using GDP/GTP alternation to control numerous vital cellular processes. Although aberrant function and regulation of GTPases are implicated in various human diseases, direct targeting of this class of proteins has proven difficult, as GTPase signaling and regulation is mediated by extensive and shallow protein interfaces. Here we report the development of inhibitors of protein–protein interactions involving Rab proteins, a subfamily of GTPases, which are key regulators of vesicular transport. Hydrocarbon‐stapled peptides were designed based on crystal structures of Rab proteins bound to their interaction partners. These modified peptides exhibit significantly increased affinities and include a stapled peptide (StRIP3) that selectively binds to activated Rab8a and inhibits a Rab8a–effector interaction in vitro. 相似文献
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Rosario Gonzlez-Muiz María ngeles Bonache María Jesús Prez de Vega 《Molecules (Basel, Switzerland)》2021,26(2)
Cyclic and macrocyclic peptides constitute advanced molecules for modulating protein–protein interactions (PPIs). Although still peptide derivatives, they are metabolically more stable than linear counterparts, and should have a lower degree of flexibility, with more defined secondary structure conformations that can be adapted to imitate protein interfaces. In this review, we analyze recent progress on the main methods to access cyclic/macrocyclic peptide derivatives, with emphasis in a few selected examples designed to interfere within PPIs. These types of peptides can be from natural origin, or prepared by biochemical or synthetic methodologies, and their design could be aided by computational approaches. Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes. 相似文献
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Constrained Peptides with Target‐Adapted Cross‐Links as Inhibitors of a Pathogenic Protein–Protein Interaction
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Dr. Gernot Hahne Dr. Christoph Rademacher Dr. Christian Ottmann Dr. Tom N. Grossmann 《Angewandte Chemie (International ed. in English)》2014,53(9):2489-2493
Bioactive conformations of peptides can be stabilized by macrocyclization, resulting in increased target affinity and activity. Such macrocyclic peptides proved useful as modulators of biological functions, in particular as inhibitors of protein–protein interactions (PPI). However, most peptide‐derived PPI inhibitors involve stabilized α‐helices, leaving a large number of secondary structures unaddressed. Herein, we present a rational approach towards stabilization of an irregular peptide structure, using hydrophobic cross‐links that replace residues crucially involved in target binding. The molecular basis of this interaction was elucidated by X‐ray crystallography and isothermal titration calorimetry. The resulting cross‐linked peptides inhibit the interaction between human adaptor protein 14‐3‐3 and virulence factor exoenzyme S. Taking into consideration that irregular peptide structures participate widely in PPIs, this approach provides access to novel peptide‐derived inhibitors. 相似文献
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Dr. Lech‐Gustav Milroy Dr. Maria Bartel Dr. Morkos A. Henen Dr. Seppe Leysen Joris M. C. Adriaans Prof. Dr. Luc Brunsveld Dr. Isabelle Landrieu Dr. Christian Ottmann 《Angewandte Chemie (International ed. in English)》2015,54(52):15720-15724
The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein–stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X‐ray crystallographic data from both stabilizer and inhibitor co‐crystal complexes of the adapter protein 14‐3‐3 to characterize, down to the atomic scale, inhibitors of the 14‐3‐3/Tau PPI, a potential drug target to treat Alzheimer’s disease. The most potent compound notably inhibited the binding of phosphorylated full‐length Tau to 14‐3‐3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer–protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14‐3‐3 and other PPIs. 相似文献
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Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity
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Dr. Ziqing Qian Dr. Xiaohua Xu Dr. Jeanine F. Amacher Prof. Dr. Dean R. Madden Prof. Dr. Estelle Cormet‐Boyaka Prof. Dr. Dehua Pei 《Angewandte Chemie (International ed. in English)》2015,54(20):5874-5878
A general strategy was developed for the intracellular delivery of linear peptidyl ligands through fusion to a cell‐penetrating peptide and cyclization of the fusion peptides via a disulfide bond. The resulting cyclic peptides are cell permeable and have improved proteolytic stability. Once inside the cell, the disulfide bond is reduced to produce linear biologically active peptides. This strategy was applied to generate a cell‐permeable peptide substrate for real‐time detection of intracellular caspase activities during apoptosis and an inhibitor for the CFTR‐associated ligand (CAL) PDZ domain as a potential treatment for cystic fibrosis. 相似文献
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Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes
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Dr. Marta Pelay‐Gimeno Adrian Glas Dr. Oliver Koch Dr. Tom N. Grossmann 《Angewandte Chemie (International ed. in English)》2015,54(31):8896-8927
Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure‐based design of PPI inhibitors through stabilizing or mimicking turns, β‐sheets, and helices. 相似文献
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Covalent Attachment of Cyclic TAT Peptides to GFP Results in Protein Delivery into Live Cells with Immediate Bioavailability
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Dr. Francesco Natale Nina Bohlke Prof. Nediljko Budisa Prof. M. Cristina Cardoso Prof. Christian P. R. Hackenberger 《Angewandte Chemie (International ed. in English)》2015,54(6):1950-1953
The delivery of free molecules into the cytoplasm and nucleus by using arginine‐rich cell‐penetrating peptides (CPPs) has been limited to small cargoes, while large cargoes such as proteins are taken up and trapped in endocytic vesicles. Based on recent work, in which we showed that the transduction efficiency of arginine‐rich CPPs can be greatly enhanced by cyclization, the aim was to use cyclic CPPs to transport full‐length proteins, in this study green fluorescent protein (GFP), into the cytosol of living cells. Cyclic and linear CPP–GFP conjugates were obtained by using azido‐functionalized CPPs and an alkyne‐functionalized GFP. Our findings reveal that the cyclic‐CPP–GFP conjugates are internalized into live cells with immediate bioavailability in the cytosol and the nucleus, whereas linear CPP analogues do not confer GFP transduction. This technology expands the application of cyclic CPPs to the efficient transport of functional full‐length proteins into live cells. 相似文献
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Back Cover: Constrained Peptides with Target‐Adapted Cross‐Links as Inhibitors of a Pathogenic Protein–Protein Interaction (Angew. Chem. Int. Ed. 9/2014)
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Dr. Gernot Hahne Dr. Christoph Rademacher Dr. Christian Ottmann Dr. Tom N. Grossmann 《Angewandte Chemie (International ed. in English)》2014,53(9):2510-2510
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A Cyclized Helix‐Loop‐Helix Peptide as a Molecular Scaffold for the Design of Inhibitors of Intracellular Protein–Protein Interactions by Epitope and Arginine Grafting
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Dr. Daisuke Fujiwara Hidekazu Kitada Masahiro Oguri Toshio Nishihara Dr. Masataka Michigami Dr. Kazunori Shiraishi Dr. Eiji Yuba Dr. Ikuhiko Nakase Haeri Im Sunhee Cho Dr. Jong Young Joung Prof. Seiji Kodama Prof. Kenji Kono Prof. Sihyun Ham Prof. Ikuo Fujii 《Angewandte Chemie (International ed. in English)》2016,55(36):10612-10615
The design of inhibitors of intracellular protein–protein interactions (PPIs) remains a challenge in chemical biology and drug discovery. We propose a cyclized helix‐loop‐helix (cHLH) peptide as a scaffold for generating cell‐permeable PPI inhibitors through bifunctional grafting: epitope grafting to provide binding activity, and arginine grafting to endow cell‐permeability. To inhibit p53–HDM2 interactions, the p53 epitope was grafted onto the C‐terminal helix and six Arg residues were grafted onto another helix. The designed peptide cHLHp53‐R showed high inhibitory activity for this interaction, and computational analysis suggested a binding mode for HDM2. Confocal microscopy of cells treated with fluorescently labeled cHLHp53‐R revealed cell membrane penetration and cytosolic localization. The peptide inhibited the growth of HCT116 and LnCap cancer cells. This strategy of bifunctional grafting onto a well‐structured peptide scaffold could facilitate the generation of inhibitors for intracellular PPIs. 相似文献
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Fabian Soltermann Eric D. B. Foley Veronica Pagnoni Martin Galpin Justin L. P. Benesch Philipp Kukura Weston B. Struwe 《Angewandte Chemie (International ed. in English)》2020,59(27):10774-10779
Interactions between biomolecules control the processes of life in health and their malfunction in disease, making their characterization and quantification essential. Immobilization‐ and label‐free analytical techniques are desirable because of their simplicity and minimal invasiveness, but they struggle with quantifying tight interactions. Here, we show that mass photometry can accurately count, distinguish by molecular mass, and thereby reveal the relative abundances of different unlabelled biomolecules and their complexes in mixtures at the single‐molecule level. These measurements determine binding affinities over four orders of magnitude at equilibrium for both simple and complex stoichiometries within minutes, as well as the associated kinetics. These results introduce mass photometry as a rapid, simple and label‐free method for studying sub‐micromolar binding affinities, with potential for extension towards a universal approach for characterizing complex biomolecular interactions. 相似文献
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Jonathan M. Lamley Carl Öster Rebecca A. Stevens Dr. Józef R. Lewandowski 《Angewandte Chemie (International ed. in English)》2015,54(51):15374-15378
Understanding the dynamics of interacting proteins is a crucial step toward describing many biophysical processes. Here we investigate the backbone dynamics for protein GB1 in two different assemblies: crystalline GB1 and the precipitated GB1–antibody complex with a molecular weight of more than 300 kDa. We perform these measurements on samples containing as little as eight nanomoles of GB1. From measurements of site‐specific 15N relaxation rates including relaxation dispersion we obtain snapshots of dynamics spanning nine orders of magnitude in terms of the time scale. A comparison of measurements for GB1 in either environment reveals that while many of the dynamic features of the protein are conserved between them (in particular for the fast picosecond–nanosecond motions), much greater differences occur for slow motions with motions in the >500 ns range being more prevalent in the complex. The data suggest that GB1 can potentially undergo a small‐amplitude overall anisotropic motion sampling the interaction interface in the complex. 相似文献
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Design of Decorin‐Based Peptides That Bind to Collagen I and their Potential as Adhesion Moieties in Biomaterials
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Dr. Stefania Federico Dr. Benjamin F. Pierce Dr. Susanna Piluso Dr. Christian Wischke Prof. Dr. Andreas Lendlein Dr. Axel T. Neffe 《Angewandte Chemie (International ed. in English)》2015,54(37):10980-10984
Mimicking the binding epitopes of protein–protein interactions by using small peptides is important for generating modular biomimetic systems. A strategy is described for the design of such bioactive peptides without accessible structural data for the targeted interaction, and the effect of incorporating such adhesion peptides in complex biomaterial systems is demonstrated. The highly repetitive structure of decorin was analyzed to identify peptides that are representative of the inner and outer surface, and it was shown that only peptides based on the inner surface of decorin bind to collagen. The peptide with the highest binding affinity for collagen I, LHERHLNNN, served to slow down the diffusion of a conjugated dye in a collagen gel, while its dimer could physically crosslink collagen, thereby enhancing the elastic modulus of the gel by one order of magnitude. These results show the potential of the identified peptides for the design of biomaterials for applications in regenerative medicine. 相似文献
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Dr. Martin Richter Alokta Chakrabarti Dr. Ivo R. Ruttekolk Dr. Burkhard Wiesner Dr. Michael Beyermann Prof. Dr. Roland Brock Prof. Dr. Jörg Rademann 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(52):16708-16715
Multivalent peptide–oligosaccharide conjugates were prepared and used to investigate the multivalency effect concerning the activity of Bid‐BH3 peptides in live cells. Dextran oligosaccharides were carboxyethylated selectively in the 2‐position of the carbohydrate units and activated for the ligation of N‐terminally cysteinylated peptides. Ligation through maleimide coupling was found to be superior to the native chemical ligation protocol. Monomeric Bid‐BH3 peptides were virtually inactive, whereas pentameric peptide conjugates induced apoptosis up to 20‐fold stronger at identical peptide concentrations. Comparison of lowly multivalent and highly multivalent peptide dextrans proved a multivalency effect in life cells which was specific for the BH3 peptide sequence. 相似文献