Mark Overhand

Publications of Mark Overhand

• Narrowing the conformational space sampled by two-domain proteins with paramagnetic probes in both domains.

  Authors: Soumyasri Dasgupta, Xiaoyu Hu, Peter H J Keizers, Wei-Min Liu, Claudio Luchinat, Malini Nagulapalli, Mark Overhand, Giacomo Parigi, Luca Sgheri, Marcellus Ubbink

  Journal of biomolecular NMR. 08/2011; 51(3):253-63.

  Calmodulin is a two-domain protein which in solution can adopt a variety of conformations upon reorientation of its domains. The maximum occurrence (MO) of a set of calmodulin conformations that areCalmodulin is a two-domain protein which in solution can adopt a variety of conformations upon reorientation of its domains. The maximum occurrence (MO) of a set of calmodulin conformations that are representative of the overall conformational space possibly sampled by the protein, has been calculated from the paramagnetism-based restraints. These restraints were measured after inclusion of a lanthanide binding tag in the C-terminal domain to supplement the data obtained by substitution of three paramagnetic lanthanide ions to the calcium ion in the second calcium binding loop of the N-terminal domain. The analysis shows that the availability of paramagnetic restraints arising from metal ions placed on both domains, reduces the MO of the conformations to different extents, thereby helping to identify those conformations that can be mostly sampled by the protein.

• Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives.

  Authors: Annemiek D Knijnenburg, Varsha V Kapoerchan, Gijsbert M Grotenbreg, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Bep Ravensbergen, Peter H Nibbering, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Bioorganic & medicinal chemistry. 06/2011; 19(11):3402-9.

  In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. ThisIn this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar side chain of the additional d-amino acid residue is positioned at the same face of the molecule as the hydrophobic side chains, and we believe that because of this compound 2 is considerably less hydrophobic than extended GS derivatives in which the strand regions are exclusively composed of l-amino acids. Using this backbone structure as our benchmark we prepared a small series of ring-extended GS analogues featuring sugar amino acid dipeptide isosteres of varied hydrophobicity at the turn region. We show that via this approach hydrophobicity of extended GS analogues can be tuned without affecting the secondary structure (as observed from NMR and CD spectra). Biological evaluation reveals that hydrophobicity correlates to cell toxicity, but still bacteriolysis is induced with GS analogues that are too hydrophilic to efficiently lyse human red blood cells.

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• Exploring the conformational and biological versatility of β-turn-modified gramicidin S by using sugar amino acid homologues that vary in ring size.

  Authors: Annemiek D Knijnenburg, Adriaan W Tuin, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Chemistry (Weinheim an der Bergstrasse, Germany). 03/2011; 17(14):3995-4004.

  Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of theMonobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties determines the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-containing peptides is solvent dependent. The derivative containing the pyranoid SAA is slightly less hydrophobic and displays a diminished haemolytic activity, but has similar antimicrobial properties as GS.

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• Evaluation of readily accessible azoles as mimics of the aromatic ring of D-phenylalanine in the turn region of gramicidin S.

  Authors: Matthijs van der Knaap, Lianne T Lageveen, Henk J Busscher, Roos Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Gijsbert A van der Marel, Herman S Overkleeft, Mark Overhand

  ChemMedChem. 03/2011; 6(5):840-7.

  The influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidin S was investigated against aThe influence of replacing the d-phenylalanine residue with substituted and unsubstituted azoles on the structure and biological activity of the antibiotic gramicidin S was investigated against a representative panel of Gram-positive and Gram-negative bacteria strains. Substituted triazole derivatives, obtained using a convergent synthetic strategy, are as active as gramicidin S, provided that any substituent on the triazole moiety is not too large. The unsubstituted triazole derivative was biologically less active than the parent natural product, gramicidin S. In general for the triazole series, the hemolytic activity could be correlated with the antibacterial activity, that is, the higher the antibacterial activity, the higher the toxicity towards blood cells. Interestingly, its imidazole counterpart showed high antibacterial activity, combined with significantly diminished hemolytic activity.

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• A comparison of triazole-forming bioconjugation techniques for constructing comb-shaped peptide-polymer bioconjugates.

  Authors: Luiz A Canalle, Matthijs van der Knaap, Mark Overhand, Jan C M van Hest

  Macromolecular rapid communications. 01/2011; 32(2):203-8.

  The grafting-to of a peptide to a side chain functional polymer was investigated using "click" chemistry. Two click reactions were compared: the copper-free strain-promoted azide-alkyneThe grafting-to of a peptide to a side chain functional polymer was investigated using "click" chemistry. Two click reactions were compared: the copper-free strain-promoted azide-alkyne 1,3-cycloaddition (SPAAC) and the traditional copper-catalyzed azide-alkyne 1,3-cycloaddition (CuAAC). For the resulting comb-shaped products, it was found that the steric bulk of the conjugation moiety used in SPAAC limits the degree of grafting for these highly dense systems, whereas CuAAC gives (near) quantitative functionalization.

• An adamantyl amino acid containing gramicidin S analogue with broad spectrum antibacterial activity and reduced hemolytic activity.

  Authors: Varsha V Kapoerchan, Annemiek D Knijnenburg, Miquel Niamat, Emile Spalburg, Albert J de Neeling, Peter H Nibbering, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Chemistry (Weinheim an der Bergstrasse, Germany). 10/2010; 16(40):12174-81.

  The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilicThe cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram-negative and Gram-positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic.

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• Sugar amino acid based peptide epoxyketones as potential proteasome inhibitors.

  Authors: Martijn D P Risseeuw, Bogdan I Florea, Gijsbert A van der Marel, Herman S Overkleeft, Mark Overhand

  Bioorganic chemistry. 10/2010; 38(5):202-9.

  This paper describes the synthesis and biological evaluation of nine epoxomicin-derived sugar amino acid containing peptide epoxyketones. The title compounds are assembled from six sugar amino acidThis paper describes the synthesis and biological evaluation of nine epoxomicin-derived sugar amino acid containing peptide epoxyketones. The title compounds are assembled from six sugar amino acid dipeptide isosteres and are synthesized using solution-phase peptide synthesis protocols. Although neither of the compounds displays inhibitory activity towards any of the proteasome active sites, our approach holds promise towards the development of structurally new proteasome inhibitors. It is likely that the central sugar amino acid dipeptide isoster needs to be designed such that it closely resemble dipeptides at position P2 and P3 in proteasome substrates inhibitors, such as the Thr-Ile dipeptide present in the lead compound, epoxomicin.

• Tuning hydrophobicity of highly cationic tetradecameric Gramicidin S analogues using adamantane amino acids.

  Authors: Annemiek D Knijnenburg, Varsha V Kapoerchan, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Bioorganic & medicinal chemistry. 09/2010; 18(23):8403-9.

  Ring extended Gramicidin S analogues containing adamantane amino acids and six cationic residues were designed and evaluated. Systematic replacement of the hydrophobic residues with adamantane aminoRing extended Gramicidin S analogues containing adamantane amino acids and six cationic residues were designed and evaluated. Systematic replacement of the hydrophobic residues with adamantane amino acids resulted in a small set of compounds with varying amphipathic character. It was found that the amphipathicity of these compounds is correlated to their biological activity. Several bacterial strains including MRSA strains were shown to be killed by the novel peptides. The most potent antibacterial peptides are tetradecameric GS analogues containing six positives charges and two adamantane moieties.

• A solution model of the complex formed by adrenodoxin and adrenodoxin reductase determined by paramagnetic NMR spectroscopy.

  Authors: Peter H J Keizers, Berna Mersinli, Wolfgang Reinle, Julia Donauer, Yoshitaka Hiruma, Frank Hannemann, Mark Overhand, Rita Bernhardt, Marcellus Ubbink

  Biochemistry. 08/2010; 49(32):6846-55.

  Lanthanide tags offer the opportunity to retrieve long-range distance information from NMR experiments that can be used to guide protein docking. To determine whether sufficient restraints can beLanthanide tags offer the opportunity to retrieve long-range distance information from NMR experiments that can be used to guide protein docking. To determine whether sufficient restraints can be retrieved for proteins with low solubility and availability, Ln tags were applied in the study of the 65 kDa membrane-associated protein complex formed by the electron carrier adrenodoxin and its electron donor, adrenodoxin reductase. The reductase is only monomeric at low concentration, and the paramagnetic iron-sulfur cluster of adrenodoxin broadens many of the resonances of nuclei in the interface. Guided by the paramagnetic restraints obtained using two Ln-tag attachment sites, protein docking yields a cluster of solutions with an rmsd of 3.2 A. The mean structure is close to the crystal structure of the cross-linked complex, with an rmsd of 4.0 A. It is concluded that with the application of Ln tags paramagnetic NMR restraints for structure determination can be retrieved even for difficult, low-concentration protein complexes.

• Gramicidin S derivatives containing cis- and trans-morpholine amino acids (MAAs) as turn mimetics.

  Authors: Varsha V Kapoerchan, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, José M Otero, Patricia Ferraces-Casais, Antonio L Llamas-Saiz, Mark J van Raaij, Joop van Doorn, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  Chemistry (Weinheim an der Bergstrasse, Germany). 03/2010; 16(14):4259-65.

  The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpinThe cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational properties of the thus obtained GS analogues (6-9) was assessed by using NMR spectroscopy and X-ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8, containing the dipeptide isostere trans-MAA 4, has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and -negative bacterial strains is better than the derivatives 6, 7 and 9.

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• Synthesis and evaluation of d-gluco-pyranocyclopropyl amines as potential glucosidase inhibitors.

  Authors: Martijn D P Risseeuw, Richard J B H N van den Berg, Wilma E Donker-Koopman, Gijs A van der Marel, Johannes M F G Aerts, Mark Overhand, Herman S Overkleeft

  Bioorganic & medicinal chemistry letters. 12/2009; 19(23):6600-3.

  In the recent past sugar-derived cyclopropylamines were proposed as structurally new glycosidase inhibitors. In this Letter we report our efforts in the synthesis of a set of alpha-glucose configuredIn the recent past sugar-derived cyclopropylamines were proposed as structurally new glycosidase inhibitors. In this Letter we report our efforts in the synthesis of a set of alpha-glucose configured oxabicyclo[4.1.0] heptanes, based on this hypothesis, bearing an amine substituent on the propyl ring and reveal that their inhibitory potential towards a range of mammalian glucosidases is modest.

• Design, synthesis and evaluation of high-affinity binders for the celiac disease associated HLA-DQ2 molecule.

  Authors: Varsha V Kapoerchan, Martina Wiesner, Ulrik Hillaert, Jan W Drijfhout, Mark Overhand, Philippe Alard, Gijs A van der Marel, Hermen S Overkleeft, Frits Koning

  Molecular immunology. 12/2009;

  Celiac disease is caused by uncontrolled CD4 T-cell responses directed to wheat-derived gluten peptides bound to the disease predisposing HLA-DQ molecules. The only available treatment is a life-longCeliac disease is caused by uncontrolled CD4 T-cell responses directed to wheat-derived gluten peptides bound to the disease predisposing HLA-DQ molecules. The only available treatment is a life-long gluten-free diet which is complicated by the widespread use of wheat-derived gluten in the food industry. As the binding of gluten-derived peptides is a prerequisite for the induction of the inflammatory T-cell response, blockers that would prevent gluten peptide binding to the HLA-DQ molecules might be used as an alternative to the gluten-free diet. In the present study we have analyzed the binding properties of a set of previously identified natural ligands for HLA-DQ2, the primary disease predisposing allele. An in silico method, Epibase, ranked these peptides and the top one, a peptide with a nine amino acid core FVAEYEPVL, was measured among these peptides as the peptide with the highest binding affinity for HLA-DQ2. In a stepwise approach we subsequently tested the impact of N-terminal extensions and systematic single amino acid substitutions within the core of this peptide which revealed that an N-terminal extension with the tripeptide sequence ADA increased binding affinity 5- to 6-fold. In addition the substitution analysis indicated which amino acids were most preferred at anchor residues in the lead peptide, generally leading to an increase of binding affinity with a factor of 2. Next we tested which combinations of such preferred amino acids yielded the best results. The combined results indicate that a peptide with sequence ADAYDYESEELFAA (core in bold) had superior binding properties. This peptide was chosen as a lead peptide for further optimization with non-natural amino acids at the p1 position, since molecular modeling indicated that none of the natural amino acids is able to optimally occupy the p1 pocket. A set of 8 non-proteinogenic amino acids was designed, synthesized and incorporated in the lead peptide (and in two control peptides) and tested for binding to HLA-DQ2. The results indicate that the effect of the incorporation of these non-proteinogenic amino acids depended on the peptide in which they were incorporated and that the maximum increase in binding affinity obtained was approximately 2-fold. Altogether lead sequences were obtained that have a binding affinity for HLA-DQ2 that is 100- to 200-fold higher compared to that of the gluten-derived peptide that has the highest affinity for HLA-DQ2. Such peptides are candidate lead peptides for further optimization. Our results, however, also indicate that in order to obtain further significant increases in binding affinity alternative approaches will have to be explored.

• Ring-Extended Derivatives of Gramicidin S with Furanoid Sugar Amino Acids in the Turn Region Have Enhanced Antimicrobial Activity.

  Authors: Annemiek D Knijnenburg, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Daan Noort, Gijsbert M Grotenbreg, Gijs A van der Marel, Herman S Overkleeft, Mark Overhand

  ChemMedChem. 10/2009;

• Bisphosphine-Functionalized Cyclic Decapeptides Based on the Natural Product Gramicidin S: A Potential Scaffold for Transition-Metal Coordination.

  Authors: Sebastian Burck, Sander G A van Assema, Bas Lastdrager, J Chris Slootweg, Andreas W Ehlers, José M Otero, Bruno Dacunha-Marinho, Antonio L Llamas-Saiz, Mark Overhand, Mark J van Raaij, Koop Lammertsma

  Chemistry (Weinheim an der Bergstrasse, Germany). 08/2009;

  The natural product Gramicidin S is a promising scaffold for novel oligopeptide-based bisphosphine ligands, combining the advantageous rigid chiral backbone with the close proximity of phosphineThe natural product Gramicidin S is a promising scaffold for novel oligopeptide-based bisphosphine ligands, combining the advantageous rigid chiral backbone with the close proximity of phosphine substituents. The required unnatural, phosphine-containing, amino acid building blocks were synthesized by means of a novel protocol that involves the enantioselective alkylation of a chiral nickel Schiff base template. Three Ni complexes were prepared with different alkyl chains between the phosphine group and the alpha-carbon atom of the incorporated glycine; the absolute stereochemistry of two of them was determined by single-crystal X-ray structure analysis. By detaching the template, enantiopure L-phosphine amino acids resulted enabling the solid-phase, stepwise construction of a linear sequence of the phosphine-modified oligopeptides. On cyclization three bisphosphine-substituted Gramicidin S analogues resulted, differing only in the size and shape of the linkage between the phosphine groups and the oligopeptides backbone. Their crystal structures suggest these species to have potential as chelating ligands.

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• Structural and biological evaluation of some loloatin C analogues.

  Authors: Adriaan W Tuin, Gijsbert M Grotenbreg, Emile Spalburg, Albert J de Neeling, Roos H Mars-Groenendijk, Gijsbert A van der Marel, Daan Noort, Herman S Overkleeft, Mark Overhand

  Bioorganic & medicinal chemistry. 08/2009;

  Loloatin C is a cyclic cationic antimicrobial peptide which is active against Gram positive as well as certain Gram negative bacteria. Unfortunately, it is equally potent against human erythrocytes.Loloatin C is a cyclic cationic antimicrobial peptide which is active against Gram positive as well as certain Gram negative bacteria. Unfortunately, it is equally potent against human erythrocytes. To probe the structure-activity relationship of this promising antibiotic peptide, amino acid substitution and/or incorporation of a constraint sugar amino acid dipeptide isoster has been applied. Six new derivatives have been synthesized using SPPS and their solution structure investigated using NMR studies. Finally, the antimicrobial and the hemolytic activities have been determined.

• Synthesis and biological evaluation of asymmetric gramicidin S analogues containing modified d-phenylalanine residues.

  Authors: Matthijs van der Knaap, Eefje Engels, Henk J Busscher, José M Otero, Antonio L Llamas-Saiz, Mark J van Raaij, Roos H Mars-Groenendijk, Daan Noort, Gijsbert A van der Marel, Herman S Overkleeft, Mark Overhand

  Bioorganic & medicinal chemistry. 08/2009;

  The synthesis of new analogues of the cationic antimicrobial peptide gramicidin S, having a modified d-phenylalanine residue, their antibacterial properties against several Gram positive and negativeThe synthesis of new analogues of the cationic antimicrobial peptide gramicidin S, having a modified d-phenylalanine residue, their antibacterial properties against several Gram positive and negative strains, as well as their hemolytic activity is reported.

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• Design, Synthesis, and Evaluation of a Lanthanide Chelating Protein Probe: CLaNP-5 Yields Predictable Paramagnetic Effects Independent of Environment.

  Authors: Peter Keizers, Athanasios Saragliadis, Yoshitaka Hiruma, Mark Overhand, Marcellus Ubbink

  Journal of the American Chemical Society. 11/2008;

  Immobilized lanthanide ions offer the opportunity to refine structures of proteins and the complexes they form by using restraints obtained from paramagnetic NMR experiments. We report the design,Immobilized lanthanide ions offer the opportunity to refine structures of proteins and the complexes they form by using restraints obtained from paramagnetic NMR experiments. We report the design, synthesis, and spectroscopic evaluation of the lanthanide chelator, Caged Lanthanide NMR Probe 5 (CLaNP-5) readily attachable to a protein surface via two cysteine residues. The probe causes tunable pseudocontact shifts, alignment, paramagnetic relaxation enhancement, and luminescence, by chelating it to the appropriate lanthanide ion. The observation of single shifts and the finding that the magnetic susceptibility tensors obtained from shifts and alignment analyses are highly similar strongly indicate that the probe is rigid with respect to the protein backbone. By placing the probe at various positions on a model protein it is demonstrated that the size and orientation of the magnetic susceptibility tensor of the probe are independent of the local protein environment. Consequently, the effects of the probe are readily predictable using a protein structure only. These findings designate CLaNP-5 as a protein probe to deliver unambiguous high quality structural restraints in studies on protein-protein and protein-ligand interactions.

• Design of azidoproline containing gluten peptides to suppress CD4+ T-cell responses associated with celiac disease.

  Authors: Varsha V Kapoerchan, Martina Wiesner, Mark Overhand, Gijs A van der Marel, Frits Koning, Herman S Overkleeft

  Bioorganic & medicinal chemistry. 03/2008; 16(4):2053-62.

  Celiac disease is an intestinal disease caused by intolerance for gluten, a common protein in food. A life-long gluten-free diet is the only available treatment. As it is well established that theCeliac disease is an intestinal disease caused by intolerance for gluten, a common protein in food. A life-long gluten-free diet is the only available treatment. As it is well established that the interaction between proline-rich gluten derived peptides and the human HLA-DQ2 molecules induces immune responses that lead to disease development, we have now designed a series of gluten peptides in which proline residues were replaced by azidoprolines. These peptides were found to bind to HLA-DQ2 with an affinity similar to that of the natural gluten peptide. Moreover, some of these peptides were found to be non-immunogenic and block gluten induced immune responses. These can thus serve as lead compounds for the development of HLA-DQ2 blocker peptides.

• Increased paramagnetic effect of a lanthanide protein probe by two-point attachment.

  Authors: Peter H J Keizers, Jean F Desreux, Mark Overhand, Marcellus Ubbink

  Journal of the American Chemical Society. 09/2007; 129(30):9292-3.

• Synthesis of alkylated sugar amino acids: conformationally restricted L-Xaa-L-Ser/Thr mimics.

  Authors: Martijn D P Risseeuw, Jaroslaw Mazurek, Arjan van Langenvelde, Gijsbert A van der Marel, Herman S Overkleeft, Mark Overhand

  Organic & biomolecular chemistry. 08/2007; 5(14):2311-4.

  Two synthetic strategies for the generation of delta-substituted pyranoid sugar amino acids (SAAs) are evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents.Two synthetic strategies for the generation of delta-substituted pyranoid sugar amino acids (SAAs) are evaluated. The first employs chiral nonracemic tert-butane sulfinamides as key reagents. Regardless of the stereochemistry of the applied sulfinamide, the product formed has a stereochemistry resembling that of a d amino acid at C7. Direct Grignard reaction on formyl-tetra-O-benzyl-beta-D-C-glucopyranoside in the second strategy and subsequent Mitsunobu inversion, yields the l,l-dipeptide isosters.