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Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.
Dual glucagon-like peptide-1/glucagon receptor agonists have emerged as promising candidates for the treatment of diabetes and obesity. Issues of degradation sensitivity and rapid renal clearance are addressed, for example, by the conjugation of peptides to fatty acid chains, promoting reversible albumin binding. We use combined dynamic and static light scattering to directly measure the self-assembly of a set of dual peptide agonists based on the exendin-4 structure with varying fatty acid chain lengths in terms of apparent molecular mass and hydrodynamic radius (R-S). We use NMR spectroscopy to gain an insight into the molecular architecture of the assembly. We investigate conformational changes of the monomeric subunits resulting from peptide self-assembly and assembly stability as a function of the fatty acid chain length using circular dichroism and fluorescence spectroscopy. Our results demonstrate that self-assembly of the exendin-4-derived dual agonist peptides is essentially driven by hydrophobic interactions involving the conjugated acyl chains. The fatty acid chain length affects assembly equilibria and the assembly stability, although the peptide subunits in the assembly retain a dynamic secondary structure. The assembly architecture is characterized by juxtaposition of the fatty acyl side chains and a hydrophobic cluster of the peptide moiety. This cluster experiences local conformational changes in the assembly compared to the monomeric unit leading to a reduction in solvent exposure. The N-terminal half of the peptide and a C-terminal loop are not in contact with neighboring peptide subunits in the assemblies. Altogether, our study contributes to a thorough understanding of the association characteristics and the tendency toward self-assembly in response to lipidation. This is important not only to achieve the desired bioavailability but also with respect to the physical stability of peptide solutions.
Racemic and highly enantioenriched 3-methoxycarbonyl, 3-carboxy, and 3-hydroxymethyl derivatives of dibenzo[6]helicene were prepared. The Langmuir layers of these helicenes were formed at the air-water interface and transferred onto solid substrates to afford Langmuir-Blodgett films, which were then studied by ambient atomic force microscopy and (chir)optical spectroscopy. Significant differences were found in the behaviour of the Langmuir layers as well as in the morphology, UV/Vis, electronic circular dichroism (ECD), and fluorescence spectra of the Langmuir-Blodgett thin films depending on the molecular chirality and nature of the polar group. The experimental results were supported by molecular dynamics simulations.
Aldol reactions play an important role in organic synthesis, as they belong to the class of highly beneficial C-C-linking reactions. Aldol-type reactions can be efficiently and stereoselectively catalyzed by the enzyme 2-deoxy-D-ribose-5-phosphate aldolase (DERA) to gain key intermediates for pharmaceuticals such as atorvastatin. The immobilization of DERA would open the opportunity for a continuous operation mode which gives access to an efficient, large-scale production of respective organic intermediates. In this contribution, we synthesize and utilize DERA/polymer conjugates for the generation and fixation of a DERA bearing thin film on a polymeric membrane support. The conjugation strongly increases the tolerance of the enzyme toward the industrial relevant substrate acetaldehyde while UV-cross-linkable groups along the conjugated polymer chains provide the opportunity for covalent binding to the support. First, we provide a thorough characterization of the conjugates followed by immobilization tests on representative, nonporous cycloolefinic copolymer supports. Finally, immobilization on the target supports constituted of polyacrylonitrile (PAN) membranes is performed, and the resulting enzymatically active membranes are implemented in a simple membrane module setup for the first assessment of biocatalytic performance in the continuous operation mode using the combination hexanal/acetaldehyde as the substrate.