Miriam Böhm

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (7)

  • Source
    Dataset: mmc2
    Daniel Tietze · Enrico Leipold · Pascal Heimer · [...] · Alesia A. Tietze
    Full-text Dataset · Jul 2016
  • Source
    Daniel Tietze · Enrico Leipold · Pascal Heimer · [...] · Alesia A. Tietze
    [Show abstract] [Hide abstract] ABSTRACT: For a large number of conopeptides basic knowledge related to structure-activity relationships is unavailable although such information is indispensable with respect to drug development and their use as drug leads. A combined experimental and theoretical approach employing electrophysiology and molecular modeling was applied for identifying the conopeptide δ-EVIA binding site at voltage-gated Na+ channels and to gain insight into its mode of action. Conopeptide δ-EVIA was synthesized and its structure was re-determined by NMR spectroscopy for molecular docking studies. Molecular docking and molecular dynamics simulation studies were performed involving the domain-IV voltage sensor in a resting conformation and part of the domain I S5 element. Molecular modeling was stimulated by functional studies, which demonstrated the importance of domains I and IV of the neuronal NaV1.7 channel for toxin action. δ-EVIA shares its binding epitope with other voltage-sensor toxins, such as the conotoxin δ-SVIE and various scorpion α-toxins. In contrast to previous _in silico_ toxin binding studies, we present here _in silico_ binding studies of a voltage-sensor toxin including the entire toxin binding site comprising the resting state of the domain-IV voltage sensor and S5 of domain I. The prototypical voltage-sensor toxin δ-EVIA is suited for the elucidation of its binding epitope; in-depth analysis of its interaction with the channel target yields information on the mode of action and might also help to unravel the mechanism of voltage-dependent channel gating and coupling of activation and inactivation.
    Full-text Article · Jun 2016 · Biochimica et Biophysica Acta (BBA) - General Subjects
  • Miriam Böhm · Charlotte A Bäuml · Kornelia Hardes · [...] · Diana Imhof
    [Show abstract] [Hide abstract] ABSTRACT: The inhibition of the final step in blood coagulation, the factor XIIIa (FXIIIa) catalyzed cross-linking of fibrin monomers, is currently still a challenge in medicinal chemistry. We report synthesis, recombinant expression, disulfide connectivity, and biological activity of tridegin, the sole existing peptide representative displaying inhibitory activity on FXIIIa. Inhibition of the enzyme by this 66-mer cysteine-rich peptide is mediated by its C-terminal sequence, while the N-terminal part comprises structural information and contributes to inhibitor binding. Either of the production strategies examined leads to the formation of different disulfide-bridged isomers indicating the requirement of the correct fold for inhibitory activity. Molecular modeling and docking studies confirm disulfide bond isomer preference with respect to binding to FXIIIa, in turn, the knowledge of the enzyme-inhibitor interactions might bring about comprehensive ideas for the design of a suitable lead structure for addressing FXIIIa.
    Article · Dec 2014 · Journal of Medicinal Chemistry
  • Pascal Heimer · Alesia A. Tietze · Miriam Böhm · [...] · Diana Imhof
    [Show abstract] [Hide abstract] ABSTRACT: The oxidation of the conotoxin μ-SIIIA in different ionic liquids was investigated, and the results were compared with those obtained in [C2mim][OAc]. Conversion of the reduced precursor into the oxidized product was observed in the protic ILs methyl- and ethylammonium formate (MAF and EAf, respectively), whereas choline dihydrogenphosphate and Ammoeng 110 failed to yield folded peptide. However, the quality and yield of the peptide obtained in MAF and EAF were lower than in the case of the product from [C2mim][OAc]. Reaction conditions (temperature, water content) also had an impact on peptide conversion. A closer look at the activities of μ-SIIIA versions derived from an up-scaled synthesis in [C2mim][OAc] revealed a significant loss of the effect on ion channel NaV1.4 relative to the buffer-oxidized peptide, whereas digestion of either μ-SIIIA product by trypsin was unaffected. This was attributed to adherence of ions from the IL to the peptide, because the disulfide connectivity is basically the same for the differentially oxidized μ-SIIIA versions.
    Article · Nov 2014 · ChemBioChem
  • M. Boehm · T. Kuehl · T. Steinmetzer · [...] · D. Imhof
    Article · Sep 2014 · Journal of Peptide Science
  • Source
    Miriam Böhm · Alesia A. Tietze · Pascal Heimer · [...] · Diana Imhof
    [Show abstract] [Hide abstract] ABSTRACT: This paper represents the final report on the results obtained during a two-years funding period within the DFG priority program 1191: Ionic liquids. The studies were focused on the interaction of ionic liquids with peptides in two distinct reactions involving cysteine residues, namely oxidative folding and native chemical ligation (NCL). Both reactions are generally performed in solution phase. With the exception of selected model compounds, the bioactive peptides used herein are rather hydrophobic and long (>20 amino acids) representatives of their respective class, e.g. conotoxins and enzyme inhibitors. Thus, ionic liquids were used as alternative media to circumvent solubility issues. We found that imidazolium-based ionic liquids, and more precisely [C(2)mim][OAc], were most suitable for both reactions being superior to conventional aqueous buffer systems in several aspects, including reaction yield and time, concentration of starting material and product as well as selectivity.
    Full-text Article · Apr 2014 · Journal of Molecular Liquids
  • Source
    Miriam Böhm · Toni Kühl · Kornelia Hardes · [...] · Diana Imhof
    [Show abstract] [Hide abstract] ABSTRACT: Tridegin, a 66-mer peptide isolated from the leech Haementeria ghilianii, is a potent inhibitor of the coagulation factor XIIIa. This paper describes the chemical synthesis of tridegin by two different strategies--solid-phase assembly and native chemical ligation--both followed by oxidation in solution phase. Tridegin and truncated analogues were examined for their activity and revealed a particular importance of the C-terminal region of the parent peptide. Based on these studies a minimal sequence required for factor XIIIa inhibition could be identified. Our data revealed that the glutamine residue at position 52 (Q52) of tridegin most likely binds to the active site of factor XIIIa and was therefore suggested to react with the enzyme. The function of the N-terminal region is also discussed, as the isolated C-terminal segment of tridegin lost its inhibitory activity rapidly in the presence of factor XIIIa, whereas this was not the case for the full-length inhibitor.
    Full-text Article · Feb 2012 · ChemMedChem