Hydrophobic zinc(II) phthalocyanine-type derivatives, solubilized in polymeric micelles (PMs), provide a befitting group of so-called nanophotosensitizers, suitable for a variety of photodynamic therapy (PDT) protocols. The factors that influence the success of such products in PDT are the location of the active cargo in the PMs and the nanocarrier-enhanced ability to safely interact with biological systems and fulfill their therapeutic functions. Therefore, the aim of this work was to determine the solubilization loci of three phthalocyanines of varying hydrophobicity, i.e., zinc(II) phthalocyanine (ZnPc), along with its tetrasulfonic acid (ZnPc-sulfo) and perfluorinated (ZnPcF) derivatives, loaded in polymeric micelles of methoxy poly(ethylene oxide)-b-poly(l-lactide) (mPEG-b-PLLA), by means of H nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) combined with ion sputtering. Furthermore, the microenvironment influence upon the chemical and physical status of the solubilized cargo in PMs, expressed by photobleaching and reactive oxygen species (ROS) generation comparing to the same properties of native cargoes in solution, was also evaluated and discussed in regards to the probing location data. The studied phthalocyanine-loaded PMs exhibited good physical stability, high drug-loading efficiency, and a size of less than ca. 150 nm with low polydispersity indices. The formation of polymeric micelles and the solubilization locus were investigated byH NMR and XPS. ZnPc localized within the PM core, whereas both ZnPcF and ZnPc-sulfo - in the corona of PMs. We proved that the cargo locus is crucial for the photochemical properties of the studied phthalocyanines; the increase in photostability and ability to generate ROS in micellar solution compared to free photosensitizer was most significant for the photosensitizer in the PM core. Our results indicate the role of the cargo location in the PM microenvironment and demonstrate that such attempts are fundamental for improving the properties of photosensitizers and their assumed efficiency as nanophotosensitizers in PDT.
Peptidotriazolamers are hybrid foldamers with features of peptides and triazolamers, containing alternation of amide bonds and 1,4-disubstituted 1
H
-1,2,3-triazoles with conservation of the amino acid side chains. We report on the synthesis of a new class of peptidomimetics, containing 1,4-disubstituted 1
H
-1,2,3-triazoles in alternation with amide bonds and the elucidation of their conformational properties in solution. Based on enantiomerically pure propargylamines bearing the stereogenic center in the propargylic position and α-azido esters, building blocks were obtained by copper-catalyzed azide-alkyne cycloaddition. With these building blocks the peptidotriazolamers were readily available by solution phase synthesis. A panel of homo- and heterochiral tetramers, hexamers, and heptamers was synthesized and the heptamer Boc-Ala-Val-Ψ[4Tz]Phe-LeuΨ[4Tz]Phe-LeuΨ[4Tz]Val-OAll as well as an heterochiral and a Gly-containing equivalent were structurally characterized by NMR-based molecular dynamics simulations using a specifically tailored force field to determine their conformational and solvation properties. All three variants adopt a compact folded conformation in DMSO as well as in water. In addition to the heptamers we predicted the conformational behavior of similar longer oligomers i.e., Boc-Ala-(AlaΨ[4Tz]Ala)
6
-OAll as well as Boc-Ala-(d-AlaΨ[4Tz]Ala)
6
-OAll and Boc-Ala-(GlyΨ[4Tz]Ala)
6
-OAll. Our calculations predict a clear secondary structure of the first two molecules in DMSO that collapses in water due to the hydrophobic character of the side chains. The homochiral compound folds into a regular helical structure and the heterochiral one shows a twisted “S”-shape, while the Gly variant exhibits no clear secondary structure.
Synthesis, structural and biological studies of pentapeptides containing two DeltaPhe residues (Z and E isomers) in position 2 and 4 in peptide chain were performed. All the investigated peptides adopted bent conformation and majority of them could exist as two different conformers in solution. Only pentapeptides, containing free N-termini appeared to act as weak inhibitors of cathepsin C with the slow-binding, competitive mechanism of inhibition, free acids being bound slightly better than their methyl esters. Results of molecular modeling suggested significant difference between peptides, depending of the type of amino acid residue in position 5 in peptide chain. Dehydropeptides containing Gly residue in this position may act as competitive slow-reacting substrates and therefore exhibit inhibitory-like properties.
The design of synthetic foldamers to selectively bind proteins is currently hindered by the limited availability of molecular data to establish key features of recognition. Previous work has described dimerization of human carbonic anhydrase II (HCA) through self-association of a quinoline oligoamide helical foldamer attached to a tightly binding HCA ligand. A crystal structure of the complex provided atomic details to explain the observed induction of single foldamer helix handedness and revealed an unexpected foldamer-mediated dimerization. Here, we investigated the detailed behavior of the HCA-foldamer complex in solution by using NMR spectroscopy. We found that the ability to dimerize is buffer-dependent and uses partially distinct intermolecular contacts. The use of a foldamer variant incapable of self-association confirmed the ability to induce helix handedness separately from dimer formation and provided insight into the dynamics of enantiomeric selection.
The promotion of protein dimerization using the aggregation properties of a protein ligand was explored and shown to produce complexes with unusual stoichiometries. Helical foldamer 2 was synthesized and bound to human carbonic anhydrase (HCA) using a nanomolar active site ligand. Crystal structures show that the hydrophobicity of 2 and interactions of its side chains lead to the formation of an HCA-2 complex in which three helices of 2 are stacked, two of them being linked to an HCA molecule. The middle foldamer in the stack can be replaced by alternate sequences 3 or 5. Solution studies by CD and NMR confirm left-handedness of the helical foldamers as well as HCA dimerization.
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