Diederichsen, Ulf

[["dc.bibliographiccitation.firstpage","4931"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","European Journal of Organic Chemistry"],["dc.bibliographiccitation.lastpage","4935"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Schmoldt, H. U."],["dc.contributor.author","Kolmar, Harald"],["dc.contributor.author","Diederichsen, Ulf"],["dc.date.accessioned","2018-11-07T10:43:45Z"],["dc.date.available","2018-11-07T10:43:45Z"],["dc.date.issued","2004"],["dc.description.abstract","An Fmoc-assisted synthesis of a 29 amino acid trypsin inhibitor (McoTI-29) is presented, which contains a non-natural guaninyl nucleo amino acid as arginine mimetic at the P1 position. This artificial amino acid functions as a conformational restricted arginine isoster with reduced basicity. The folded cyclotide McoTI-II open-chain variant McoTI-29 has been synthesized from a linear precursor by in situ oxidation. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)"],["dc.identifier.doi","10.1002/ejoc.200400440"],["dc.identifier.isi","000225535400024"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/47127"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-v C H Verlag Gmbh"],["dc.relation.issn","1434-193X"],["dc.title","FMOC-assisted synthesis of a 29-residue cystine-knot trypsin inhibitor containing a guaninyl amino acid at the P1-position"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","33"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","ChemBioChem"],["dc.bibliographiccitation.lastpage","37"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Schmoldt, Hans-Ulrich"],["dc.contributor.author","Gabrijelcic-Geiger, Dusica"],["dc.contributor.author","Wentzel, Alexander"],["dc.contributor.author","Frauendorf, Holm"],["dc.contributor.author","Sommerhoff, Christian P."],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Kolmar, Harald"],["dc.date.accessioned","2018-11-07T11:19:11Z"],["dc.date.available","2018-11-07T11:19:11Z"],["dc.date.issued","2008"],["dc.identifier.doi","10.1002/cbic.200700452"],["dc.identifier.isi","000252292200005"],["dc.identifier.pmid","18058774"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/55212"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-v C H Verlag Gmbh"],["dc.relation.issn","1439-4227"],["dc.title","Head-to-tail cyclized cystine-knot peptides by a combined recombinant and chemical route of synthesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4177"],["dc.bibliographiccitation.issue","20"],["dc.bibliographiccitation.journal","Organic & Biomolecular Chemistry"],["dc.bibliographiccitation.lastpage","4185"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Empting, Martin"],["dc.contributor.author","Fabritz, Sebastian"],["dc.contributor.author","Daneschdar, Matin"],["dc.contributor.author","Frauendorf, Holm"],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Kolmar, Harald"],["dc.date.accessioned","2018-11-07T08:35:17Z"],["dc.date.available","2018-11-07T08:35:17Z"],["dc.date.issued","2009"],["dc.description.abstract","Here we describe the facile generation of tetravalent peptide conjugates via a copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) using a cyclic peptide template as a versatile conjugation scaffold. This stable and rigid framework is a conformationally constrained cyclic beta-sheet decorated with spatially defined alkyne moieties that serve as selectively addressable coupling sites. The proposed method allows for the effective coupling of unprotected peptide monomers in water at room temperature within comparatively short reaction times. The resulting conjugates display the ligands in an oriented manner, thus allowing for multivalent interactions with given target molecules, which may contribute to enhanced affinity and specificity. In addition, the selected scaffold offers an orthogonal coupling site for the incorporation of fluorescent labels or radioligands."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [KO 1390/9-1]; BMBF"],["dc.identifier.doi","10.1039/b908261a"],["dc.identifier.isi","000270320300007"],["dc.identifier.pmid","19795056"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/18028"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Royal Soc Chemistry"],["dc.relation.issn","1477-0520"],["dc.title","Application of copper(I) catalyzed azide-alkyne [3+2] cycloaddition to the synthesis of template-assembled multivalent peptide conjugates"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1301"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Biological Chemistry"],["dc.bibliographiccitation.lastpage","1306"],["dc.bibliographiccitation.volume","386"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Schmoldt, H. U."],["dc.contributor.author","Gabrijelcic-Geiger, D."],["dc.contributor.author","Le Nguyen, D."],["dc.contributor.author","Sommerhoff, Christian P."],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Kolmar, Harald"],["dc.date.accessioned","2018-11-07T10:53:43Z"],["dc.date.available","2018-11-07T10:53:43Z"],["dc.date.issued","2005"],["dc.description.abstract","MCoTl-I and MCoTl-II from the seeds of Momordica cochinchinensis are inhibitors of trypsin-like proteases and the only known members of the large family of squash inhibitors that are cyclic and contain an additional loop connecting the amino- and the carboxy-terminus. To investigate the contribution of macrocycle formation to biological activity, we synthesized a set of open-chain variants of MCoTl-II that lack the cyclization loop and contain various natural and non-natural amino acid substitutions in the reactive-site loop. Upon replacement of P1 lysine residue #10 within the open-chain variant of MCoTl-II by the non-natural isosteric nucleo amino acid AlaG[beta-(guanin-9-yl)-L-alanine], a conformationally restricted arginine mimetic, residual inhibitory activity was detected, albeit reduced by four orders of magnitude. While the cyclic inhibitors MCoTl-I and MCoTl-II were found to be very potent trypsin inhibitors, with picomolar inhibition constants, the open-chain variants displayed an approximately 10-fold lower affinity. These data suggest that the formation of a circular backbone in the MCoTI squash inhibitors results in enhanced affinity and therefore is a determinant of biological activity."],["dc.identifier.doi","10.1515/BC.2005.148"],["dc.identifier.isi","000233965400011"],["dc.identifier.pmid","16336125"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/49407"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Walter De Gruyter & Co"],["dc.relation.issn","1431-6730"],["dc.title","Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","167"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Journal of Molecular Biology"],["dc.bibliographiccitation.lastpage","175"],["dc.bibliographiccitation.volume","395"],["dc.contributor.author","Sommerhoff, Christian P."],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Schmoldt, Hans-Ulrich"],["dc.contributor.author","Gabrijelcic-Geiger, Dusica"],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Kolmar, Harald"],["dc.date.accessioned","2018-11-07T08:46:48Z"],["dc.date.available","2018-11-07T08:46:48Z"],["dc.date.issued","2010"],["dc.description.abstract","Here we report the design, chemical and recombinant synthesis, and functional properties of a series of novel inhibitors of human mast cell tryptase beta, a protease of considerable interest as a therapeutic target for the treatment of allergic asthma and inflammatory disorders. These inhibitors are derived from a linear variant of the cyclic cystine knot miniprotein MCoTI-II, originally isolated from the seeds of Momordica cochinchmensis. A synthetic cyclic miniprotein that bears additional positive charge in the loop connecting the N- and C-termini inhibits all monomers of the tryptase beta tetramer with an overall equilibrium dissociation constant K(1) of 1 nM and thus is one of the most potent proteinaceous inhibitors of tryptase beta described to date. These cystine knot miniproteins may therefore become valuable scaffolds for the design of a new generation of tryptase inhibitors. (C) 2009 Elsevier Ltd. All rights reserved."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [KO 1390/9-1, DI 542/6-1]"],["dc.identifier.doi","10.1016/j.jmb.2009.10.028"],["dc.identifier.isi","000274351900013"],["dc.identifier.pmid","19852971"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/20785"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Academic Press Ltd- Elsevier Science Ltd"],["dc.relation.issn","0022-2836"],["dc.title","Engineered Cystine Knot Miniproteins as Potent Inhibitors of Human Mast Cell Tryptase beta"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e3298"],["dc.bibliographiccitation.journal","Journal of Peptide Science"],["dc.contributor.author","Becker, Bastian"],["dc.contributor.author","Englert, Simon"],["dc.contributor.author","Schneider, Hendrik"],["dc.contributor.author","Yanakieva, Desislava"],["dc.contributor.author","Hofmann, Sarah"],["dc.contributor.author","Dombrowsky, Carolin"],["dc.contributor.author","Macarrón Palacios, Arturo"],["dc.contributor.author","Bitsch, Sebastian"],["dc.contributor.author","Elter, Adrian"],["dc.contributor.author","Meckel, Tobias"],["dc.contributor.author","Kugler, Benedikt"],["dc.contributor.author","Schirmacher, Anastasyia"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Kolmar, Harald"],["dc.date.accessioned","2021-02-19T11:06:25Z"],["dc.date.available","2021-02-19T11:06:25Z"],["dc.date.issued","2021-01-17"],["dc.description.abstract","The development of novel biotherapeutics based on peptides and proteins is often limited to extracellular targets, because these molecules are not able to reach the cytosol. In recent years, several approaches were proposed to overcome this limitation. A plethora of cell-penetrating peptides (CPPs) was developed for cytoplasmic delivery of cell-impermeable cargo molecules. For many CPPs, multimerization or multicopy arrangement on a scaffold resulted in improved delivery but also higher cytotoxicity. Recently, we introduced dextran as multivalent, hydrophilic polysaccharide scaffold for multimerization of cell-targeting cargoes. Here, we investigated covalent conjugation of a CPP to dextran in multiple copies and assessed the ability of resulted molecular hybrid to enter the cytoplasm of mammalian cells without largely compromising cell viability. As a CPP, we used a novel, low-toxic cationic amphiphilic peptide L17E derived from M-lycotoxin. Here, we show that cell-penetrating properties of L17E are retained upon multivalent covalent linkage to dextran. Dextran-L17E efficiently mediated cytoplasmic translocation of an attached functional peptide and a peptide nucleic acid (PNA). Moreover, a synthetic route was established to mask the lysine side chains of L17E with a photolabile protecting group thus opening avenues for light-triggered activation of cellular uptake."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.identifier.doi","10.1002/psc.3298"],["dc.identifier.pmid","33458922"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/79835"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.relation.eissn","1099-1387"],["dc.relation.issn","1075-2617"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes."],["dc.title","Multivalent dextran hybrids for efficient cytosolic delivery of biomolecular cargoes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2158"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","ACS Chemical Biology"],["dc.bibliographiccitation.lastpage","2165"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Dickgiesser, Stephan"],["dc.contributor.author","Rasche, Nicolas"],["dc.contributor.author","Nasu, Daichi"],["dc.contributor.author","Middel, Stephen"],["dc.contributor.author","Hoerner, Sebastian"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Kolmar, Harald"],["dc.date.accessioned","2018-11-07T09:52:16Z"],["dc.date.available","2018-11-07T09:52:16Z"],["dc.date.issued","2015"],["dc.description.abstract","Over the past decade, DNA and RNA aptamers have attracted keen research interest due to their ability to specifically bind targets of therapeutic relevance. However, their application is often hampered by a short serum half-life and missing effector functions. Conjugation of aptamers to antibody Fc fragments could improve pharmacokinetics, enable immune effector mechanisms, and provide an option for the introduction of desired payloads (e.g., toxins or fluorescent dyes). We developed a modular scaffold-supported system based on human IgG1 Fc fragments, which allows for its dual functionalization with moieties of interest. In our approach, two bioorthogonal, enzyme-mediated reactions were used in combination with oxime ligation and self-assembly based on PNA-DNA base pairing. Thus, an engineered synthetic peptide nucleic acid (PNA) oligomer was coupled to the C-termini of the Fc dimer upon sequence-specific sortase A-mediated transpeptidation. Hybridization of the resulting Fc-PNA conjugate with a tailored DNA aptamer that binds cancer-related hepatocyte growth factor receptor (c-MET) led to a hybrid construct which showed strong and specific binding to c-MET and was readily internalized by c-MET-overexpressing cells. To install an additional orthogonally addressable site, aldehyde tag technology was applied followed by oxime ligation with an aminooxy-bearing fluorescent dye as model cargo. Delivery of fluorescent probe specifically to c-MET-overexpressing cells was confirmed by flow cytometry. Our approach can provide access to engineered aptamer-Fc conjugates with desired target specificity and cytotoxic payloads."],["dc.description.sponsorship","Merck Serono Innovation Cup initiative; Merck Serono Innovation Cup"],["dc.identifier.doi","10.1021/acschembio.5b00315"],["dc.identifier.isi","000361867200023"],["dc.identifier.pmid","26131766"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36085"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Chemical Soc"],["dc.relation.issn","1554-8937"],["dc.relation.issn","1554-8929"],["dc.title","Self-Assembled Hybrid Aptamer-Fc Conjugates for Targeted Delivery: A Modular Chemoenzymatic Approach"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","54"],["dc.bibliographiccitation.journal","BMC Structural Biology"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Heitz, Annie"],["dc.contributor.author","Avrutina, Olga"],["dc.contributor.author","Le-Nguyen, Dung"],["dc.contributor.author","Diederichsen, Ulf"],["dc.contributor.author","Hernandez, Jean-Francois"],["dc.contributor.author","Gracy, Jerome"],["dc.contributor.author","Kolmar, Harald"],["dc.contributor.author","Chiche, Laurent"],["dc.date.accessioned","2018-11-07T11:07:59Z"],["dc.date.available","2018-11-07T11:07:59Z"],["dc.date.issued","2008"],["dc.description.abstract","Background: Present in various species, the knottins (also referred to as inhibitor cystine knots) constitute a group of extremely stable miniproteins with a plethora of biological activities. Owing to their small size and their high stability, knottins are considered as excellent leads or scaffolds in drug design. Two knottin families contain macrocyclic compounds, namely the cyclotides and the squash inhibitors. The cyclotide family nearly exclusively contains head-to-tail cyclized members. On the other hand, the squash family predominantly contains linear members. Head-to-tail cyclization is intuitively expected to improve bioactivities by increasing stability and lowering flexibility as well as sensitivity to proteolytic attack. Results: In this paper, we report data on solution structure, thermal stability, and flexibility as inferred from NMR experiments and molecular dynamics simulations of a linear squash inhibitor EETI-II, a circular squash inhibitor MCoTI-II, and a linear analog lin-MCoTI. Strikingly, the head-to-tail linker in cyclic MCoTI-II is by far the most flexible region of all three compounds. Moreover, we show that cyclic and linear squash inhibitors do not display large differences in structure or flexibility in standard conditions, raising the question as to why few squash inhibitors have evolved into cyclic compounds. The simulations revealed however that the cyclization increases resistance to high temperatures by limiting structure unfolding. Conclusion: In this work, we show that, in contrast to what could have been intuitively expected, cyclization of squash inhibitors does not provide clear stability or flexibility modification. Overall, our results suggest that, for squash inhibitors in standard conditions, the circularization impact might come from incorporation of an additional loop sequence, that can contribute to the miniprotein specificity and affinity, rather than from an increase in conformational rigidity or protein stability. Unfolding simulations showed however that cyclization is a stabilizing factor in strongly denaturing conditions. This information should be useful if one wants to use the squash inhibitor scaffold in drug design."],["dc.identifier.doi","10.1186/1472-6807-8-54"],["dc.identifier.isi","000265066600001"],["dc.identifier.pmid","19077275"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12498"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/52694"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1472-6807"],["dc.rights.access","openAccess"],["dc.rights.holder","Heitz et al."],["dc.title","Knottin cyclization: impact on structure and dynamics"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]