9 research outputs found
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Self-assembled RGD dehydropeptide hydrogels for drug delivery applications
Peptide-based self-assembled hydrogels have triggered remarkable research interest in recent years owing to their biocompatibility and biomimetic properties and responsiveness, which warrant many technological and biomedical applications. Dehydrodipeptides N-capped with naproxen emerged from our research as effective hydrogelators endowed with resistance to proteolysis. Dehydrodipeptide-based hydrogels are promising nanocarriers for drug delivery applications. In this work, we demonstrate that dehydrodipetide Npx-L-Ala-Z-ΔPhe-OH can be deployed as a minimalist hydrogelator module for synthesizing a gelating construct Npx-L-Ala-Z-ΔPhe-G-R-G-D-G-OH bearing a GRGDG adhesion motif. The self-assembly of the peptide construct and the drug delivery properties of the hydrogel were studied in this work. The peptide construct showed no toxicity towards a fibroblast cell line expressing the αvβ3 integrin. Docking studies suggest that the hydrogelator block does not interfere with the recognition of the RGD motif by the integrin receptor. The self-assembly seems to be directed by intermolecular naphthalene π–π stacking interactions, with the peptide backbone assuming a random coil conformation both in solution and in the gel phase. TEM and STEM imaging revealed that the hydrogel is made of entangled bundles of long thin fibres (width circa 23 nm). The hydrogel exhibits viscoelastic properties, thermo-reversibility and recovery after mechanical fluidization. FRET studies showed that curcumin incorporated into the hydrogel interacts non-covalently with the hydrogel fibrils. Delivery of curcumin from the hydrogel into Nile red loaded model membranes (SUVs) was demonstrated by FRET. Naproxen N-capped dehydrodipeptides are efficacious minimalist hydrogelator modules for obtaining hydrogels functionalized with peptide ligands for cell receptors. These hydrogels are potential nanocarriers for drug delivery
Grafting of adipic anhydride to carbon nanotubes through a Diels-Alder cycloaddition/oxidation cascade reaction
Accepted ManuscriptDifferent reactions have been reported for the successful functionalization of carbon nanotubes (CNT). The Diels-Alder cycloaddition is recognized as a plausible chemical approach, but few reports are known where this strategy has been used. In this study, the functionalization was performed by 1,3-butadiene generated from 3-sulfolene under heating conditions in diglyme. This simple and easily scalable method resulted in functionalized CNT with mass losses of 10 - 23 % by thermogravimetric analysis (nitrogen atmosphere). The functionalization was also supported by acid-base titration, elemental analysis, temperature programmed desorption and X-ray photoelectron spectroscopy. The high content in oxygen detected on the CNT surface was assigned to anhydride formation due to a cascade oxidation of the alkene groups generated in the cycloaddition reaction. The complete evolution of the alkene leads to a grafting density of 4.2 mmol g-1 for the anhydride moiety. Ab-initio calculations in CNT model systems indicate that the Diels-Alder addition of butadiene is a feasible process and that subsequent oxidation reactions may result in the formation of the anhydride moiety. The presence of the anhydride group is a valuable asset for grafting a multitude of complex molecules, namely through the nucleophilic addition of amines.Centro de Química and Instituto de Polímeros e Compósitos of the University of Minho and Fundação para a Ciência e Tecnologia (FCT) through the Portuguese NMR network (RNRMN), the Project F-COMP-01-0124-FEDER-022716 (ref. FCT PEst-C/QUI/UI0686/2011) FEDER-COMPETE, Project PEst-C/CTM/LA0025/2013 (Strategic Project - LA 25-2013-2014) and also Project Scope UID/CEC/00319/2013. TG Castro acknowledges FCT for a doctoral grant (SFRH/BD/79195/2011) RF Araújo for a Post-doc grant (SFRH/BPD/88920/2012) and MMF also acknowledges FCT through the program Ciência 2008. Access to computing resources funded by the Project "Search-ON2: Revitalization of HPC infrastructure of UMinho" (NORTE-07-0162-FEDER-000086) is also gratefully acknowledged
Modeling of Peptaibol Analogues Incorporating Nonpolar α,α-Dialkyl Glycines Shows Improved α‑Helical Preorganization and Spontaneous Membrane Permeation
In
this study, we investigate the effect of nine noncanonical α,α-dialkyl
glycines on the structure, dynamics, and membrane permeation properties
of a small peptaibol, peptaibolin. The noncanonical amino acids under
study are Aib (α-amino isobutyric acid), Deg (α,α-diethyl
glycine), Dpg (α,α-dipropyl glycine), Dibg (α,α-di-isobutyl
glycine), Dhg (α,α-dihexyl glycine), DΦg (α,α-diphenyl
glycine), Db<sub><i>z</i></sub>g (α,α-dibenzyl
glycine), Ac<sub>6</sub>c (α,α-cyclohexyl glycine), and
Dmg (α,α-dihydroxymethyl glycine). It is hypothesized
that these amino acids are able to induce well-defined secondary structures
in peptidomimetics. To investigate this hypothesis, we designed new
peptaibolin peptidomimetics by replacing the native Aib positions
with a new α,α-dialkyl glycine. We show that Dhg and Ac<sub>6</sub>c noncanonical amino acids are able to induce α-helix
secondary structures of peptaibolin in water, which are not present
in the native structure. We also demonstrate that the α,α-dialkyl
glycines increase the membrane permeability of peptaibolin in 1-palmitoyl-2-oleoylphosphatidylcholine
(POPC) membranes. However, there is no apparent correlation between
increased helicity and membrane permeability. In summary, we show
that some α,α-dialkyl glycines under study induce the
formation of α-helix secondary structures in peptaibolin and
promote spontaneous membrane permeation. Our findings increase the
knowledge of the membrane permeability and folding of peptides incorporating α,α-dialkyl
glycines
Mechanism of Hair Curling via Laccase-Assisted Tyrosine Grafting Using BSA as a Model Protein
Commercial hair perming uses strong reducing agents and harms hair fiber’s quality even human health. In this study, tyrosine is adopted as a cross-linking agent between thiols and/or amines as the shape-changing of hair involves the breakage of disulfide bonds and the rearrangement of new bonds between keratin molecules. To investigate the mechanism of keratin cross-linking, bovine serum albumin (BSA) is used as a model protein. Disulfide bonds in BSA are successfully reduced by L-cysteine to provide free thiols. Four new cross-linked peptides are formed inter- or intra-BSA monomers, indicating that tyrosine can be adopted as a cross-linking agent not only between amines but also between thiols. Moreover, curling of Asian hair is conducted using tyrosine as a perming agent by the laccase-assisted reaction. The optimized operational conditions are hair with L-cysteine pre-treatment (50.0 mM) followed by laccase-assisted grafting with 3.0 mM tyrosine. The reshaped hair performed a better perming performance than commercial perming product before washing, although a lower perming efficiency after washing. The curling process could be accomplished without strength loss of hair fibers and with a blow-drier easily. Hence, this new methodology may lead to the development of a gentle and user-friendly approach in the hair care industry
Synthesis of Novel 2,9-Disubstituted-6-morpholino Purine Derivatives Assisted by Virtual Screening and Modelling of Class I PI3K Isoforms
The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling cascades in a wide variety of cancers. In the last 15 years, there has been an increase in the search for selective inhibitors of the four class I isoforms of PI3K, as they demonstrate better specificity and reduced toxicity in comparison to existing inhibitors. A ligand-based and target-based rational drug design strategy was employed to build a virtual library of 105 new compounds. Through this strategy, the four isoforms were compared regarding their activity pocket availability, amino acid sequences, and prone interactions. Additionally, a known active scaffold was used as a molecular base to design new derivatives. The virtual screening of the resultant library toward the four isoforms points to the obtention of 19 selective inhibitors for the PI3Kα and PI3Kγ targets. Three selective ligands, one for α-isoform and two for γ-isoform, present a ∆ (∆Gbinding) equal or greater than 1.5 Kcal/mol and were identified as the most promising candidates. A principal component analysis was used to establish correlations between the affinity data and some of the physicochemical and structural properties of the ligands. The binding modes and interactions established by the selective ligands in the active centre of the α and γ isoforms of PI3K were also investigated. After modelling studies, a synthetic approach to generate selective ligands was developed and applied in synthesising a set of derivatives that were obtained in good to excellent yield
Conformational and Thermodynamic Properties of Non-Canonical α,α-Dialkyl Glycines in the Peptaibol Alamethicin: Molecular Dynamics Studies
In
this work, we investigate the structure, dynamic and thermodynamic
properties of noncanonical disubstituted amino acids (α,α-dialkyl
glycines), also known as non-natural amino acids, in the peptaibol
Alamethicin. The amino acids under study are Aib (α-amino isobutyric
acid or α-methyl alanine), Deg (α,α-diethyl glycine),
Dpg (α,α-dipropyl glycine), Dibg (α,α-di-isobutyl
glycine), Dhg (α,α-dihexyl glycine), DΦg (α,α-diphenyl
glycine), Db<sub><i>z</i></sub>g (α,α-dibenzyl glycine),
Ac<sub>6</sub>c (α,α-cyclohexyl glycine), and Dmg (α,α-dihydroxymethyl
glycine). It is hypothesized that these amino acids are able to induce
well-defined secondary structure in peptidomimetics. To test this
hypothesis, new peptidomimetics of Alamethicin were constructed by
replacing the native Aib positions of Alamethicin by one or more new
α,α-dialkyl glycines. Dhg and Ac<sub>6</sub>c demonstrated
the capacity to induce well-defined α-helical structures. Dhg
and Ac<sub>6</sub>c also promote the thermodynamic stabilization of
these peptides in a POPC model membrane and are better alternatives
to the Aib in Alamethicin. These noncanonical amino acids also improved
secondary structure properties, revealing preorganization in water
and maintenance of α helical structure in POPC. We show that
it is possible to optimize the helicity and thermodynamic properties
of native Alamethicin, and we suggest that these amino acids could
be incorporated in other peptides with similar structural effect
Addressing the Structural Organization of Silicone Alternatives in Formulations by Molecular Dynamics Simulations and a Novel Equilibration Protocol
The world of cosmetics is an always-evolving field with constant updates on its formulation components. The current reality asks for an ever-increasing need for natural and sustainable replacements for synthetic compounds in all fields of modern consumer products. However, the research and development stages of finding these alternatives can be an expensive, time-consuming, and often wasteful process that turns this task into a laborious procedure. This study introduces the development of a computational methodology that will aid the research of silicone alternatives, disclosing their structural performance in a formulation. Additionally, an equilibration protocol was developed to measure the distribution and densities of these silicone alternatives to determine how they behave in relation to their counterparts, using molecular dynamics simulations. Two systems were tested, A and B, where the former is composed of one ester (Dipentaerythrityl Hexa C5 Acid Ester) and the latter by an ester combined with an alkane (Triheptanoin and C13-Isoalkane); all three molecules are commercially available and widely used. Both systems were subjected to a 3-step thermal regulation strategy. The systems went through an initial simulation at 25 °C and at 70 °C, then a temperature switch took place (25 °C « 70 °C), then a shock to 200 °C, and finally a Simulated Annealing protocol reaching 250 °C. In the end, all systems converged towards micelle-like structures. These results come to further ascertain the position of computational chemistry and Molecular Dynamics Simulations as an important part of R&D processes in modern sciences and investigation