Self-assembly of thyminyl l-tryptophanamide (TrpT) building blocks for the potential development of drug delivery nanosystems

Abstract

The design, synthesis and characterization of a novel nucleoamino acid derivative based on an l-tryptophanamide functionalised with a thymine nucleobase (named TrpT) is here described. The novel construct’s tendency to self-assemble into supramolecular networks in aqueous solution was demonstrated by dynamic light scattering (DLS), circular dichroism (CD), fluorescence and UV spectroscopic measurements. TrpT nanoaggregates showed good stability (up to 5 h) at 140 µM and proved to comprise species of mean hydrodynamic diameter 330 nm and a homogeneous size distribution; scanning electron microscopy (SEM) analysis further revealed these to be spherical-shaped assemblies. The ability of TrpT nanoaggregates to bind curcumin, selected as a model anticancer drug, was also evaluated and its release was monitored over time by confocal microscopy. Molecular docking studies were performed on both TrpT self-assembly and curcumin-loaded nanoaggregates suggesting that the phytomolecule can be accommodated in the interior of the supramolecular network via hydrophobic (π−π and π-alkyl) interactions; the formation of TrpT-curcumin adducts may improve the polarity of the highly-hydrophobic curcumin with a resulting logP closer to the optimal values expected for a good drug bioavailability, as estimated by the ADMETlab software. Finally, the high stability of TrpT nanoassembly in human serum, and the absence of significant toxic effects on human model cells in a cell viability assay, were also demonstrated. Despite its thymine-based scaffold, TrpT was shown not to bind adenine-bearing nucleic acids, suggesting that this interaction is hindered by its intrinsic propensity to self-assemble in preference to forming A-T base pairings. Instead, TrpT was able to interact with a serum protein such as bovine serum albumin (BSA), known to improve the bloodstream transportation and bioavailability of its cargo. Collectively, our findings support the potential use of TrpT for the development of new drug delivery systems. Graphical abstract

Interaction of Laurusides 1 and 2 with the 3C-like Protease (Mpro) from Wild-Type and Omicron Variant of SARS-CoV-2: A Molecular Dynamics Study

“…These structures were then used as templates to create whole models of the systems, filling the structural gaps, by homology modelling with MODELLER 9.22 program [ 50 ]. The three-dimensional structures of the two laurusides compounds were obtained by MOLVIEW ( , accessed on 9 February 2023) in analogy to other literature examples [ 51 , 52 ], saved as .pdb files, and manually complexed into the M pro variants using the binding pose of Nirmatrelvir in PDB 7TLL as a guide [ 47 ]. In particular, the coordinates of the Nirmatrelvir were used for the binding pocket definitions in order to insert both the laurusides, upon superimposition of the two variant models on the 7TLL X-ray structure of Nirmatrelvir in complex with Omicron M pro .…”

Self-Assembling Peptide SCIBIOIII Hydrogel for Three-Dimensional Cell Culture That Promotes Wound Healing in Diabetic Mice

“…Self-assembling peptides (SAPs) are functional polymer nanomaterials synthesized from natural amino acids [ 9 ]. Additionally, synthetic peptides, including nucleopeptides [ 10 ], are able to self-assemble, leading to important biological properties [ 11 , 12 ]. Nucleopeptides are currently being investigated for the innovative opportunities offered for tissue engineering applications [ 13 ].…”

Tryptophan-PNA gc Conjugates Self-Assemble to Form Fibers

“…23 Recently, a molecule composed of L-tryptophan conjugated at its N-terminus with a thymine through a methylene carbonyl linker was found to be able to self-assemble and produce spherical aggregates, which can entrap curcumin. 24 The presence of WW might change photophysical properties of PNA conjugates.…”

“…It is reported that conjugation of the WW peptide to a DNA 12-mer results in the formation of aggregates, whose morphology is concentration-dependent . Recently, a molecule composed of l -tryptophan conjugated at its N-terminus with a thymine through a methylene carbonyl linker was found to be able to self-assemble and produce spherical aggregates, which can entrap curcumin . The presence of WW might change photophysical properties of PNA conjugates.…”