
Interactions of long-chain polyamines with silica studied by molecular dynamics simulations and solid-state NMR spectroscopy.
Maria Montagna, Stephan Ingmar Brückner, Arezoo Dianat, Rafael Gutierrez, Fabian Daus, Armin Geyer, Eike Brunner, Gianaurelio Cuniberti. Langmuir 2020, 36, 11600-11609.
DOI: 10.1021/acs.langmuir.0c02157
Supporting Information
Abstract The investigation of molecular interactions between silica phases and organic components is crucial for elucidating the main steps involved in the biosilica mineralization process. In this respect, the structural characterization of the organic/inorganic interface is particularly useful for a deeper understanding of the dominant mechanisms of biomineralization. In this work, we have investigated the interaction of selectively 13C- and 15N-labeled atoms of organic long-chain polyamines (LCPAs) with 29Si-labeled atoms of a silica layer at the molecular level. In particular, silica/LCPA nanocomposites were analyzed by solid-state NMR spectroscopy in combination with all-atom molecular dynamics simulations. Solid-state NMR experiments allow the determination of 29Si–15N and 29Si–13C internuclear distances, providing the parameters for direct verification of atomistic simulations. Our results elucidate the relevant molecular conformations as well as the nature of the interaction between the LCPA and a silica substrate. Specifically, distances and second moments suggest a picture compatible with (i) LCPA completely embedded in the silica phase and (ii) the charged amino groups located in close vicinity of silanol groups.
(No graphical abstract available)
MON-185 ACTH-derived peptide antagonists as an alternative treatment strategy for congenital adrenal hyperplasia.
J. Endocrin. Soc. 2020, 4, A298-A299. Tina Schubert, Lennart Nicke, André Schanze, Nicole Reisch, Armin Geyer, Katrin Koehler, Angela Huebner.
DOI: 10.1210/jendso/bvaa046.589
Abstract Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by different enzyme deficiencies in the steroid hormone synthesis leading to a disturbed cortisol biosynthesis. The medical treatment of CAH includes suboptimal ACTH-suppressing high glucocorticoid doses to reduce adrenal hyperplasia and overproduction of androgens. These inappropriate corticoid substitutions are often associated with undesirable side effects such as arterial hypertension, growth failure and obesity. Since the current therapy of patients with CAH is often unsatisfactory, innovative treatment options are required.
The aim of our study was to specifically block the melanocortin 2 receptor (MC2R) signaling pathway as an alternative treatment strategy for CAH. We tested ACTH-derived selective peptides with incorporation of various synthetic non-natural amino acids in the activation motif of ACTH. To study the antagonistic activity of the peptides, cAMP production of MC2R/MRAP stably transfected human embryonic kidney (HEK) 293 cells were measured. All new synthesized peptide antagonists reduced ACTH-stimulated MC2R activity as competitive inhibitors indicated by a reduced in vitro cAMP response. Cells pre-incubated with peptide LNP009 showed the most efficient blockade of the MC2R and the highest shift of EC50 of ACTH (33.8 nM ± 0.08 vs. 7.3 nM ± 0.09). LNP009 was additionally tested for specificity concerning the other known melanocortin receptors and showed no antagonistic effect up to 1 μM on MC3, MC4 or MC5 receptor transiently transfected HEK 293 cells. To further investigate the inhibitory effect of our most potent antagonist peptide LNP009 on the steroid hormone response, we assessed steroidogenic enzyme expression of the human adrenocortical tumor cell line NCI-H295RA and performed mass spectrometry analyzes of steroids in the cell culture supernatant. Pre-incubation with LNP009 reduced the expression of the genes CYP21A2, CYP11B1 and HSD3B2 in NCI-H295RA cells and significantly reduced the synthesis of aldosterone (P=0.046; n=3), cortisol (P=0.020; n=3) and corticosterone (P=0.035; n=3).
With the successful blocking of the ACTH binding and signal transduction by our antagonistic peptides, we anticipate an alternative approach for optimizing the treatment of CAH patients lacking the side effects of the currently used ACTH-suppressing corticoid therapy.

Phosphate-silica interactions in diatom biosilica and synthetic composites studied by rotational echo double resonance (redor) nmr spectroscopy.
Langmuir 2020, 36, 4332-4338.Felicitas Kolbe, Fabian Daus, Armin Geyer, Eike Brunner.
DOI: 10.1021/acs.langmuir.0c00336
Supporting information
Abstract Biosilica is a biogenic composite material produced by organisms like diatoms. Various biomolecules are tightly attached or incorporated into biosilica. Examples are special proteins termed silaffins and long-chain polyamines (LCPAs). Presumably, these biomolecules are involved in the biosilica formation process. Silaffins are highly phosphorylated zwitterions with LCPAs post-translationally attached to lysine residues. In the present work, we use distance-dependent solid-state NMR experiments, especially the 31P{29Si} Rotational Echo Double Resonance (REDOR) technique, to study the environment of phosphate moieties in biosilica and in vitro synthesized SiO2-based composites. In contrast to the heterogeneous mixtures of biomolecules found in native biosilica, the described in vitro silicification experiments make use of a single synthetic phosphopeptide and an LCPA of well-defined and uniform structure. The heteronuclear correlations measured from these silica composites provide reliable 31P–29Si dipolar second moments and information about the distribution of the phosphopeptide within the silica material. The calculated second moment indicates close contact between phosphopeptides and silica. The phosphopeptides are incorporated into the silica composite in a disperse manner. Moreover, the REDOR data acquired for diatom biosilica also imply that phosphate groups are part of the silica–organic interface in this material.

Defining the mobility range of a hinge-type connection using molecular dynamics and metadynamics
Plos One 2020 15(4):e0230962 Philip Horx, Armin Geyer
DOI:10.1371/journal.pone.0230962
Supporting Information
Abstract A designed disulfide-rich β-hairpin peptide that dimerizes spontaneously served as a hinge-type connection between proteins. Here, we analyze the range of dynamics of this hinge dimer with the aim of proposing new applications for the DNA-encodable peptide and establishing guidelines for the computational analysis of other disulfide hinges. A recent structural analysis based on nuclear magnetic resonance spectroscopy and ion mobility spectrometry revealed an averaged conformation in the hinge region which motivated us to investigate the dynamic behavior using a combination of molecular dynamics simulation, metadynamics and free energy surface analysis to characterize the conformational space available to the hinge. Principal component analysis uncovered two slow modes of the peptide, namely, the opening and closing motion and twisting of the two β-hairpins assembling the hinge. Applying a collective variable (CV) that mimics the first dominating mode, led to a major expansion of the conformational space. The description of the dynamics could be achieved by analysis of the opening angle and the twisting of the β-hairpins and, thus, offers a methodology that can also be transferred to other derivatives. It has been demonstrated that the hinge peptide’s lowest energy conformation consists of a large opening angle and strong twist but is separated by small energy barriers and can, thus, adopt a closed and untwisted structure. With the aim of proposing further applications for the hinge peptide, we simulated its behavior in the sterically congested environment of a four-helix bundle. Preliminary investigations show that one helix is pushed out and a three-helix bundle forms. The insights gained into the dynamics of the tetra-disulfide peptide and analytical guidelines developed in this study may contribute to the understanding of the structure and function of more complex hinge-type proteins, such as the IgG antibody family.

Comparing the hinge-type mobility of natural and designed intermolecular bi-disulfide domains
Front. Chem. 2020, 8, 25 Philip Horx, Armin Geyer
DOI: 10.3389/fchem.2020.00025
Supporting Information
Abstract A pair of intermolecular disulfide bonds connecting two protein domains restricts their relative mobility in a systematic way. The bi-disulfide hinge cannot rotate like a single intermolecular disulfide bond yet is less restrained than three or more intermolecular disulfides which restrict the relative motion to a minimum. The intermediate mobility of bi-disulfide linked domains is characterized by their dominating opening and closing modes comparable to the mechanics of a door hinge on the macroscopic scale. Here we compare the central hinge region of Immunoglobulin G1 (IgG1) which is highly conserved among different species, with a recently designed hinge-type motif CHWECRGCRLVC from our lab, that was successfully used for the dimerization of the IgG1/κ-ab CL4 monocolonal antibody (mab). The minimal length of these synthetic hinges comprises only 12 amino acids, rendering them ideal models for computational studies. Well-tempered metadynamics was performed to adequately describe the available conformational space defined by the different hinges. In spite of the differences in amino acid composition and ring sizes, there are characteristic similarities of designed and natural hinges like the dependent mobility of the individual strands of each hinge domain.

The role of phosphopeptides in the biomineralization of silica
Org. Biomol. Chem. 2020, 18, 700-706 Fabian Daus, Erik Pfeifer, Kevin Seipp, Norbert Hampp, Armin Geyer
DOI: 10.1039/c9ob02438g
Supporting Information
Abstract We investigated the silicification activity of hyperphosphorylated peptides in combination with long-chain polyamines (LCPA). The bioinspired in vitro silicification experiments with peptides containing different amounts of phosphorylated serines showed structure–activity dependence by altering the amount and morphology of the silica precipitate. Our study provides an explanation for the considerable metabolic role of diatoms in the synthesis of hyperphosphorylated poly-cationic peptides such as natSil-1A1. The efficient late-stage phosphorylation of peptides yielded a synthetic heptaphosphopeptide whose silicification properties resemble those of natSil-1A1. As opposed to this, unphosphorylated poly-cationic peptides or LCPA require concentrations above 1 mM for silicification. Hyperphosphorylated peptides showed a linear dependence between the amount of dissolved peptides and the amount of precipitated silica in the concentration range below 1 mM. Under mildly acidic conditions and short precipitation times, the concentration of the added LCPA determined the size of the silica spheres.

The synthesis, characterization, cytotoxic activity assessment and structure–activity relationship of 4-aryl-6-(2,5-dichlorothiophen-3-yl)-2-methoxypyridine-3-carbonitriles
Molecules 2019, 24, 4072-4083 Mahmoud Al-Refai, Mohammad M. Ibrahim, Mohamad Nurul Azmi, Hasnah Osman, Mohamad Hafizi Abu Bakar, Armin Geyer
DOI: 10.3390/molecules24224072
Supplementary Material
Abstract A series of 2-methoxypyridine-3-carbonitrile (5a–i)-bearing aryl substituents were successfully synthesized in good yields by the condensation of chalcones (4a–i) with malononitrile in basic medium. The condensation process, in most cases, offers a route to a variety of methoxypyridine derivatives (6a–g) as side products in poor yields. All new compounds were fully characterized using different spectroscopic methods. Mass ESI-HMRS measurements were also performed. Furthermore, these compounds were screened for their in vitro cytotoxicity activities against three cancer cell lines; namely, those of the liver (line HepG2), prostate (line DU145) and breast (line MBA-MB-231). The cytotoxicity assessment revealed that compounds 5d, 5g, 5h and 5i exhibit promising antiproliferative effects (IC50 1–5 µM) against those three cancer cell lines.

Reversible covalent end-capping of collagen model peptides
Chem. Eur. J. 2019, 25, 14278-14283 Christoph Priem, Armin Geyer
DOI: org/10.1002/chem.201903460
Supporting Information
Abstract The combination of supramolecular aggregation of collagen model peptides with reversible covalent end‐capping of the formed triple helix in a single experimental set‐up yielded minicollagens, which were characterized by a single melting temperature. In spite of the numerous possible reaction intermediates, a specific synthetic collagen with a leading, middle and trailing strand is formed in a highly cooperative self‐assembly process.

Directed C(sp3)−H arylation of tryptophan: transformation of the directing group into an activated amide
Chem. Sci. 2019, 10, 8634-8641. Lennart Nicke, Philip Horx, Klaus Harms, Armin Geyer
DOI: 10.1039/c9sc03440d
Supporting Information
Abstract The he 8-aminoquinoline (8AQ) directed C(sp3)–H functionalization was applied in the synthesis of β-arylated tryptophan derivatives. The laborious protecting group reorganization towards α-amino acids compatible for solid phase peptide synthesis (SPPS) was cut short by the transformation of the directing group into an activated amide, which was either used directly in peptide coupling or in the gram scale synthesis of storable Fmoc-protected amino acids for SPPS. In this work, directed C–H activation and nonplanar amide chemistry complement each other for the synthesis of hybrids between phenylalanine and tryptophan with restricted side chain mobility.

Side chain orientation of tryptophan analogs determines agonism and inverse agonism in short ghrelin peptides
ChemMedChem 2019, 14, 1849-1855. Lennart Nicke, Ronny Müller, Armin Geyer, Sylvia Els‐Heindl
DOI: 10.1002/cmdc.201900409
Supporting Information
Abstract We describe two synthetic amino acids with inverted side chain stereochemistry, which induce opposite biological activity. Phe4 is an important part of the activation motif of ghrelin, and in short peptide inverse agonists such as KwFwLL‐NH2, the aromatic core is necessary for inactivation of the receptor. To restrict indole/phenyl mobility and simultaneously strengthen the interaction between peptide and receptor, we exchanged the natural monoaryl amino acids for diaryl amino acids derived from tryptophan. By standard solid‐phase peptide synthesis, each of them was inserted into ghrelin or in the aromatic core of the inverse agonist. Both ghrelin analogues showed nanomolar activity, indicating sufficient space to accommodate the additional side chain. In contrast, diaryl amino acids in the inverse agonist had considerable influence on receptor signaling. Whereas the introduction of Wsf maintains inverse agonism of the peptide, Wrf shifts the receptor more to active states and can induce agonism depending on its introduction site.
![[Scheme 1]](data:image/gif;base64,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)
Synthesis, characterization, crystal structure and supramolecularity of ethyl (E)-2-cyano-3-(3-methylthiophen-2-yl)acrylate and a new polymorph of ethyl (E)-2-cyano-3-(thiophen-2-yl)acrylate
Acta Cryst. 2019, E75, 1357-1361. Mahmoud Al-Refai, Basem F. Ali, Ala´a B. Said, Armin Geyer, Michael Marsch, Klaus Harms
DOI: 10.1107/S2056989019011435
Supporting Information
Abstract The synthesis, crystal structure and structural motif of two thiophene-based cyanoacrylate derivatives, namely, ethyl (E)-2-cyano-3-(3-methylthiophen-2-yl)acrylate (1), C11H11NO2S, and ethyl (E)-2-cyano-3-(thiophen-2-yl)acrylate (2), C10H9NO2S, are reported. Derivative 1 crystallized with two independent molecules in the asymmetric unit, and derivative 2 represents a new monoclinic (C2/m) polymorph. The molecular conformations of 1 and the two polymorphs of 2 are very similar, as all non-H atoms are planar except for the methyl of the ethyl groups. The intermolecular interactions and crystal packing of 1 and 2 are described and compared with that of the reported monoclinic (C2/m) polymorph of derivative 2 [Castro Agudelo et al. (2017). Acta Cryst. E73, 1287–1289].
![[Scheme 1]](data:image/gif;base64,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)
3-(2,5-dichlorothiophen-3-yl)-5-(2,4-dimethoxyphenyl)-1-methyl-4,5-dihydro-1H-pyrazole.
IUCrData 2019, 4, x191046. Mohammad M. Ibrahim, Mahmoud Al-Refai, Basem F. Ali, Armin Geyer, Klaus Harms, Michael Marsch
DOI: org/10.1107/S2414314619010460
Supporting Information
Abstract In the title compound, C16H16Cl2N2O2S, the pyrazole ring has an envelope conformation with the C atom bearing the phenyl ring being the flap. The dihedral angles between the central pyrazole ring (all atoms) and pendant thiophene and phenyl rings are 2.00 (14) and 81.49 (12)°, respectively. In the crystal, weak C—H
O, Cl
π and π–π stacking interactions link the molecules into a three-dimensional network.

Synthesis, characterization and cytotoxicity of new nicotinonitriles and their furo[2,3-b]pyridine derivatives.
J. Iran. Chem. Soc. 2019, 16, 715-722. Mohammad M. Ibrahim, Mahmoud Al-Refai, Mohamad Nurul Azmi, Hasnah Osman, Mohamad Hafizi Abu Bakar, Armin Geyer
DOI: org/10.1007/s13738-018-1549-y
Supporting Information
Abstract The present research work describes the synthesis of new series of nicotinonitrile (2) and furo[2,3-b]pyridine (3) heterocycles bearing thiophene substituent. The nicotinonitrile derivatives were prepared from the corresponding 3-cyano-(2H)-pyridones (1a–f) in excellent yields. The ring cyclization of the nicotinonitrile derivatives (2a–f) in the presence of sodium methoxide provided the furo[2,3-b]pyridines (3a–f) in moderate to good yields. All the newly synthesized compounds were characterized by extensive NMR analysis data, including 1D-NMR experiments (1H and 13C) and 2D-NMR experiments (COSY, HMBC, HSQC), as well as HRESIMS data. All the final products were subjected for cytotoxic activity against five different tumour cell lines including HeLa (cervical), DU145 (prostate), HepG2 (liver), MDA-MB-231 (breast-ER negative) and MCF7 (breast-ER positive), in addition to HSF1184 (normal human fibroblast) using the MTT assay. Compounds 2d and 3e were found to exhibit promising cytotoxicity with IC50 of < 20 µM against all different tested tumour cell lines. In addition, these compounds showed high selectivity (40–287 folds) for tumour cells over normal cells.

Diamondoid Amino Acid-based Peptide Kinase A Inhibitors
ChemMedChem 2019, 14, 663-672. Janis Müller, Romina A. Kirschner, Jan‐Philipp Berndt, Tobias Wulsdorf, Alexander Metz, Radim Hrdina, Peter R. Schreiner, Armin Geyer, Gerhard Klebe
DOI: 10.1002/cmdc.201800779
Supporting Information
Abstract The incorporation of diamondoid amino acids (DAAs) into peptide‐like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA‐containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid‐phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids. Affinity and binding pose are largely conserved. One variant showed 6.5‐fold potency improvement, most likely related to its increased side chain lipophilicity. A second variant exhibited slightly decreased affinity presumably due to loss of hydrogen‐bond contacts to surrounding water molecules of the first solvation shell.

Conceptional design of self-assembling bisubstrate-like inhibitors of protein kinase a resulting in a boronic acid glutamate linkage
ACS Omega 2019, 4, 775-784. Janis Müller, Romina A. Kirschner, Armin Geyer, Gerhard Klebe
DOI: 10.1021/acsomega.8b02364
Supporting Information
Abstract The spontaneous esterification of boronic acids with polyols provides a promising opportunity to generate self-assembled bisubstrate-like inhibitors within the binding pocket of cAMP-dependent protein kinase (PKA). As a first substrate component, we designed amino acids, which have either a boronic acid or ribopyranose side chain and introduced them to the substrate-like peptide protein kinase inhibitor (PKI). The second component was derived from the active-site inhibitor Fasudil, which was functionalized with phenylboronic acid. NMR spectroscopy in dimethylsulfoxide proved spontaneous reversible condensation of both components. Reinforced by the protein environment, both separately bound substrates were expected to react via boronic-ester formation bridging the two binding sites of PKA. Multiple crystal structures of PKA with bound PKIs, positionally modified with residues such as a ribopyranosylated serine and threonine or a phenylboronic acid attached to lysine via amide bonds, were determined with the phenylboronic acid-linked Fasudil. Although PKA accepts both inhibitors simultaneously, the expected covalent attachment between both components was not observed. Instead, spontaneous reaction of the terminal boronic acid group of the modified Fasudil with the carboxylate of Glu127 was detected once the latter residue is set free from a strong salt bridge formed with arginine by the original peptide inhibitor PKI. Thus, the desired self-assembly reaction occurs spontaneously in the protein environment by an unexpected carboxylic acid boronate complex. To succeed with our planned self-assembly reaction between both substrate components, we have to redesign the required reaction partners more carefully to finally yield the desired bisubstrate-like inhibitors in the protein environment.