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1.
ACS Nano ; 14(6): 7425-7434, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32401485

RESUMO

Incorporation of fluorinated moieties in polymeric nanoparticles has been shown in many instances to increase their uptake by living cells and, hence, has proven to be a useful approach to enhancing delivery to cells. However, it remains unclear how incorporation of fluorine affects critical transport processes, such as interactions with membranes, intracellular transport, and tumor penetration. In this study, we investigate the influence of fluorine on transport properties using a series of rationally designed poly(oligo(ethylene glycol) methyl ether acrylate)-block-perfluoropolyether (poly(OEGA)m-PFPE) copolymers. Copolymers with different fluorine contents were prepared and exhibit aggregate in solution in a manner dependent on the fluorine content. Doxorubicin-conjugated poly(OEGA)20-PFPE nanoparticles with lower fluorine content exist in solution as unimers, leading to greater exposure of hydrophobic PFPE segments to the cell surface. This, in turn, results in greater cellular uptake, deeper tumor penetration, as well as enhanced therapeutic efficacy compared to that with the micelle-state nanoaggregates (poly(OEGA)10-PFPE and poly(OEGA)5-PFPE) with higher fluorine content but with less PFPE exposed to the cell membranes. Our results demonstrate that the aggregation behavior of these fluorinated polymers plays a critical role in internalization and transport in living cells and 3D spheroids, providing important design criteria for the preparation of highly effective delivery agents.

2.
Colloids Surf B Biointerfaces ; 193: 111100, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32408262

RESUMO

Understanding the interaction of ions with fatty acids is important to identify their roles in various bioprocesses and to build novel biomimetic systems. In this study, the molecular organization of palmitic acid (PA) films on alkaline buffer solutions (pH 7.4) with and without divalent Ca2+ was measured at a constant surface area using Langmuir troughs coupled with microscopy and X-ray interfacial techniques. Without Ca2+, PA molecules remained a monolayer organization; however, with Ca2+, formation of the inverted bilayers of PA-Ca2+ superstructures caused a spontaneous 2D to 3D transformation under no compression due to the strong interaction between PA and the divalent cation. Self-assembly of this highly-organized inverted bilayer superstructure involved a two-step process of nucleation and nuclei growth. During nucleation, densely packed PA and Ca2+ monolayer firstly corrugated and some of PA and Ca2+ molecules ejected out from the monolayer; the ejected molecules then reorganized and formed the inverted bilayer nuclei. Nucleation was followed by nuclei growth, during which PA and Ca2+ in the monolayer kept integrating into the inverted bilayer structure through molecule migration and PA rotation around Ca2+.

3.
ACS Nano ; 14(4): 5143-5147, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32286790

RESUMO

Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.


Assuntos
Betacoronavirus/efeitos dos fármacos , Química Computacional , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Simulação de Dinâmica Molecular , Peptídeos , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Humanos , Pandemias , Peptídeos/química , Peptídeos/uso terapêutico , Peptidil Dipeptidase A/efeitos dos fármacos , Conformação Proteica , Conformação Proteica em alfa-Hélice
4.
Sci Adv ; 6(5): eaax9318, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064341

RESUMO

Viral infections kill millions of people and new antivirals are needed. Nontoxic drugs that irreversibly inhibit viruses (virucidal) are postulated to be ideal. Unfortunately, all virucidal molecules described to date are cytotoxic. We recently developed nontoxic, broad-spectrum virucidal gold nanoparticles. Here, we develop further the concept and describe cyclodextrins, modified with mercaptoundecane sulfonic acids, to mimic heparan sulfates and to provide the key nontoxic virucidal action. We show that the resulting macromolecules are broad-spectrum, biocompatible, and virucidal at micromolar concentrations in vitro against many viruses [including herpes simplex virus (HSV), respiratory syncytial virus (RSV), dengue virus, and Zika virus]. They are effective ex vivo against both laboratory and clinical strains of RSV and HSV-2 in respiratory and vaginal tissue culture models, respectively. Additionally, they are effective when administrated in mice before intravaginal HSV-2 inoculation. Lastly, they pass a mutation resistance test that the currently available anti-HSV drug (acyclovir) fails.

5.
J Am Chem Soc ; 142(4): 1832-1837, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31895555

RESUMO

ß-Hairpin peptides present great potential as antagonists against ß-sheet-rich protein surfaces, of which wide and flat geometries are typically "undruggable" with small molecules. Herein, we introduce a peptide-dendrimer conjugate (PDC) approach that stabilizes the ß-hairpin structure of the peptide via intermolecular forces and the excluded volume effect as well as exploits the multivalent binding effect. Because of the synergistic advantages, the PDCs based on a ß-hairpin peptide isolated from an engineered programmed death-1 (PD-1) protein showed significantly higher affinity (avidity) to their binding counterpart, programmed death-ligand 1 (PD-L1), as compared to free peptides (by up to 5 orders of magnitude). The enhanced binding kinetics with high selectivity was translated into an improved immune checkpoint inhibitory effect in vitro, at a level comparable to (if not better than) that of a full-size monoclonal antibody. The results demonstrate the potential of the PDC system as a novel class of inhibitors targeting ß-strand-rich protein surfaces, such as PD-1 and PD-L1, displaying its potential as a new cancer immunotherapy platform.

6.
ACS Nano ; 14(2): 1694-1706, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31944667

RESUMO

Most natural biomolecules may exist in either of two enantiomeric forms. Although in nature, amino acid biopolymers are characterized by l-type homochirality, incorporation of d-amino acids in the design of self-assembling peptide motifs has been shown to significantly alter enzyme stability, conformation, self-assembly behavior, cytotoxicity, and even therapeutic activity. However, while functional metabolite assemblies are ubiquitous throughout nature and play numerous important roles including physiological, structural, or catalytic functions, the effect of chirality on the self-assembly nature and function of single amino acids is not yet explored. Herein, we investigated the self-assembly mechanism of amyloid-like structure formation by two aromatic amino acids, phenylalanine (Phe) and tryptophan (Trp), both previously found as extremely important for the nucleation and self-assembly of aggregation-prone peptide regions into functional structures. Employing d-enantiomers, we demonstrate the critical role that amino acid chirality plays in their self-assembly process. The kinetics and morphology of pure enantiomers is completely altered upon their coassembly, allowing to fabricate different nanostructures that are mechanically more robust. Using diverse experimental techniques, we reveal the different molecular arrangement and self-assembly mechanism of the dl-racemic mixtures that resulted in the formation of advanced supramolecular materials. This study provides a simple yet sophisticated engineering model for the fabrication of attractive materials with bionanotechnological applications.

7.
J Am Chem Soc ; 142(1): 327-334, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31782986

RESUMO

For decades, chemists have strived to mimic the intricate design and diverse functions of naturally occurring systems through the bioinspired synthesis of programmable inorganic nanomaterials. The development of thiol-capped gold nanoparticles (AuNPs) has driven advancement in this area; however, although versatile and readily accessible, hybrid AuNPs are rarely atomically precise, which limits control over their surface topology and therefore the study of complex structure-function relationships. Here, we present a bottom-up approach to the systematic assembly of atomically precise hybrid nanoclusters employing a strategy that mimics the synthetic ease with which thiol-capped AuNPs are normally constructed, while producing well-defined covalent nanoscale assemblies with diverse surface topologies. For the first time, using a structurally characterized cluster-based organometallic building block, we demonstrate the systematic synthesis of nanoclusters with multivalent binding capabilities to complex protein targets.

8.
Materials (Basel) ; 12(24)2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31817494

RESUMO

Advanced thermomechanical hot rolling is becoming a widely used technology for the production of fine-grained spring steel. Different rapid phase transformations during the inductive heat treatment of such steel causes the inhomogeneous mixture of martensitic, bainitic, and austenitic phases that affects the service properties of the steel. An important task is to assess the amount of retained austenite and its distribution over the cross-section of the inductive quenched and tempered wire in order to evaluate the mechanical properties of the material. Three different analytical methods were used for the comparative quantitative assessment of the amount of retained austenite in both the core and rim areas of the sample cross-section: neutron diffraction-for the bulk of the material, Mössbauer spectroscopy-for measurement in a surface layer, and the metallographic investigations carried by the EBSD. The methods confirmed the excessive amount of retained austenite in the core area that could negatively affect the plasticity of the material.

9.
Sci Rep ; 9(1): 17804, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31780663

RESUMO

Blocking the formation, growth, and breaking of amyloid fibrils by synthetic nanosystems could provide a treatment of neurodegenerative diseases. With this in mind, here atomistic molecular dynamics simulations are used to screen for nanoparticles (NPs), covered with different mixtures of ligands, including positively and negatively charged ligands, Aß40-cut-peptide, and synthetic inhibitor ligands, in their selective coupling to Aß40 peptides and their fibrils. The simulations reveal that only Aß40-cut-peptide-covered NPs have strong and selective coupling to Aß40 monomers. On the other hand, positive, positive-neutral, Janus, and peptide NPs couple to the beta sheet surfaces of Aß40 fibrils and only the negative-neutral NPs couple to the fibril tips.

10.
Bioconjug Chem ; 30(10): 2594-2603, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31498600

RESUMO

Multivalent protein-protein interactions serve central roles in many essential biological processes, ranging from cell signaling and adhesion to pathogen recognition. Uncovering the rules that govern these intricate interactions is important not only to basic biology and chemistry but also to the applied sciences where researchers are interested in developing molecules to promote or inhibit these interactions. Here we report the synthesis and application of atomically precise inorganic cluster nanomolecules consisting of an inorganic core and a covalently linked densely packed layer of saccharides. These hybrid agents are stable under biologically relevant conditions and exhibit multivalent binding capabilities, which enable us to study the complex interactions between glycosylated structures and a dendritic cell lectin receptor. Importantly, we find that subtle changes in the molecular structure lead to significant differences in the nanomolecule's protein-binding properties. Furthermore, we demonstrate an example of using these hybrid nanomolecules to effectively inhibit protein-protein interactions in a human cell line. Ultimately, this work reveals an intricate interplay between the structural design of multivalent agents and their biological activities toward protein surfaces.

11.
Inorg Chem ; 58(16): 10516-10526, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31247818

RESUMO

Redox-active proanions of the type B12(OCH2Ar)12 [Ar = C6F5 (1), 4-CF3C6H4 (2), 3,5-(CF3)2C6H3 (3)] are introduced in the context of an experimental and computational study of the visible-light-initiated polymerization of a family of styrenes. Neutral, air-stable proanions 1-3 were found to initiate styrene polymerization through single-electron oxidation under blue-light irradiation, resulting in polymers with number-average molecular weights (Mn) ranging from ∼6 to 100 kDa. Shorter polymer products were observed in the majority of experiments, except in the case of monomers containing 4-X (X = F, Cl, Br) substituents on the styrene monomer when polymerized in the presence of 1 in CH2Cl2. Only under these specific conditions are longer polymers (>100 kDa) observed, strongly supporting the formulation that reaction conditions significantly modulate the degree of ion pairing between the dodecaborate anion and cationic chain end. This also suggests that 1-3 behave as weakly coordinating anions (WCA) upon one-electron reduction because no incorporation of the cluster-based photoinitiators is observed in the polymeric products analyzed. Overall, this work is a conceptual realization of a single reagent that can serve as a strong photooxidant, subsequently forming a WCA.

12.
J Phys Chem Lett ; 10(13): 3592-3597, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31184895

RESUMO

The configurations of nanoparticles (NPs) floating on liquid surfaces can be largely affected by the NP shapes in combination with different NP-liquid coupling strengths. Here, the behavior of ligated nanocubes (NCs) on liquid surfaces is studied as an example of such NP floating by analytical methods and molecular dynamics simulations. Depending on the NC-liquid coupling strength, NCs can sit on the liquid surface (weak), be partly immersed in a tilted orientation (intermediate), or be fully immersed except for the top facet (strong). The simulations reveal that configurations of clusters of self-assembled NCs on liquid surfaces can be even more complex and also determined by the NC-liquid and NC-NC coupling strengths, thus providing a rich spectrum of possible superstructures formed.

13.
Mol Pharm ; 16(4): 1678-1693, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30860853

RESUMO

A novel unconventional supramolecular oligo-cationic structure (Agm6-M-PEG-OCH3) has been synthesized to yield high efficiency therapeutic oligonucleotide (ON) delivery. Agm6-M-PEG-OCH3 was obtained by a multistep protocol that included the conjugation of agmatine (Agm) moieties to maltotriose (M), which was further derivatized with one poly(ethylene glycol) (PEG) chain. Gel electrophoresis analysis showed that the 19 base pairs dsDNA model ON completely associates with Agm6-M-PEG-OCH3 at 3 N/P molar ratio, which is in agreement with the in silico molecular predictions. Isothermal titration calorimetry (ITC) analyses showed that the Agm6-M-PEG-OCH3/ON association occurs through a combination of mechanisms depending on the N/P ratios resulting in different nanostructures. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) revealed that the Agm6-M-PEG-OCH3/ON polyplexes have rod-shape structure with a mean diameter of 50-75 nm and aspect ratio depending on the N/P ratio. The polyplexes were stable over time in buffer, while a slight size increase was observed in the presence of serum proteins. Cell culture studies showed that neither Agm6-M-PEG-OCH3 nor polyplexes displayed cytotoxic effects. Cellular uptake depended on the cell line and polyplex composition: cellular internalization was higher in the case of MCF-7 and KB cells compared to MC3T3-E1 cells and polyplexes with smaller aspect ratio were taken-up by cells more efficiently than polyplexes with higher aspect ratio. Finally, preliminary studies showed that our novel carrier efficiently delivered ONs into cells providing gene silencing.


Assuntos
Portadores de Fármacos/química , Guanidina/química , Nanoestruturas/química , Oligonucleotídeos/química , Polietilenoglicóis/química , Polímeros/química , Proliferação de Células , Humanos , Nanoestruturas/administração & dosagem , Neoplasias/genética , Neoplasias/terapia , Oligonucleotídeos/administração & dosagem , Polímeros/administração & dosagem , Células Tumorais Cultivadas
14.
J Am Chem Soc ; 141(5): 1949-1960, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30595017

RESUMO

The reversible photoisomerization of azobenzene has been utilized to construct a plethora of systems in which optical, electronic, catalytic, and other properties can be controlled by light. However, owing to azobenzene's hydrophobic nature, most of these examples have been realized only in organic solvents, and systems operating in water are relatively scarce. Here, we show that by coadsorbing the inherently hydrophobic azobenzenes with water-solubilizing ligands on the same nanoparticulate platforms, it is possible to render them essentially water-soluble. To this end, we developed a modified nanoparticle functionalization procedure allowing us to precisely fine-tune the amount of azobenzene on the functionalized nanoparticles. Molecular dynamics simulations helped us to identify two distinct supramolecular architectures (depending on the length of the background ligand) on these nanoparticles, which can explain their excellent aqueous solubilities. Azobenzenes adsorbed on these water-soluble nanoparticles exhibit highly reversible photoisomerization upon exposure to UV and visible light. Importantly, the mixed-monolayer approach allowed us to systematically investigate how the background ligand affects the switching properties of azobenzene. We found that the nature of the background ligand has a profound effect on the kinetics of azobenzene switching. For example, a hydroxy-terminated background ligand is capable of accelerating the back-isomerization reaction by more than 6000-fold. These results pave the way toward the development of novel light-responsive nanomaterials operating in aqueous media and, in the long run, in biological environments.

15.
Nat Mater ; 18(2): 99-101, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643238

Assuntos
Nanoporos , DNA
16.
Adv Mater ; 31(10): e1807285, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30644148

RESUMO

Bacterial type IV pili (T4P) are polymeric protein nanofibers that have diverse biological roles. Their unique physicochemical properties mark them as a candidate biomaterial for various applications, yet difficulties in producing native T4P hinder their utilization. Recent effort to mimic the T4P of the metal-reducing Geobacter sulfurreducens bacterium led to the design of synthetic peptide building blocks, which self-assemble into T4P-like nanofibers. Here, it is reported that the T4P-like peptide nanofibers efficiently bind metal oxide particles and reduce Au ions analogously to their native counterparts, and thus give rise to versatile and multifunctional peptide-metal nanocomposites. Focusing on the interaction with Au ions, a combination of experimental and computational methods provides mechanistic insight into the formation of an exceptionally dense Au nanoparticle (AuNP) decoration of the nanofibers. Characterization of the thus-formed peptide-AuNPs nanocomposite reveals enhanced thermal stability, electrical conductivity from the single-fiber level up, and substrate-selective adhesion. Exploring its potential applications, it is demonstrated that the peptide-AuNPs nanocomposite can act as a reusable catalytic coating or form self-supporting immersible films of desired shapes. The films scaffold the assembly of cardiac cells into synchronized patches, and present static charge detection capabilities at the macroscale. The study presents a novel T4P-inspired biometallic material.


Assuntos
Nanopartículas Metálicas/química , Nanocompostos/química , Nanofibras/química , Peptídeos/química , Materiais Biocompatíveis/química , Condutividade Elétrica , Fímbrias Bacterianas , Geobacter
17.
Nat Chem ; 11(4): 359-366, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30664718

RESUMO

Transport at the molecular scale is a prerequisite for the development of future molecular factories. Here, we have designed oligoanionic molecular sliders on polycationic tracks that exploit Brownian motion and diffusive binding to transport cargo without using a chemical fuel. The presence of the polymer tracks increases the rate of bimolecular reactions between modified sliders by over two orders of magnitude. Molecular dynamics simulations showed that the sliders not only diffuse, but also jump and hop surprisingly efficiently along polymer tracks. Inspired by acetyl-coenzyme A transporting and delivering acetyl groups in many essential biochemical processes, we developed a new and unconventional type of catalytic transport involving sliders (including coenzyme A) picking up, transporting and selectively delivering molecular cargo. Furthermore, we show that the concept of diffusive binding can also be utilized for the spatially controlled transport of chemical groups across gels. This work represents a new concept for designing functional nanosystems based on random Brownian motion.


Assuntos
Polímeros/química , Calorimetria , Catálise , Difusão , Cinética , Simulação de Dinâmica Molecular , Eletricidade Estática
18.
Nanoscale ; 11(5): 2299-2305, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30662983

RESUMO

Micelles formed through the aggregation of amphiphilic block copolymers are ideal drug nanocarriers. Despite their importance in nanomedicine, the detailed mechanisms through which micelles form and copolymers encapsulate the target nanomaterials are unclear. Here, using in situ liquid cell transmission electron microscopy imaging, we capture both the dynamics of micelle formation and their encapsulation of gold nanoparticles (NPs) in an aqueous solution. Our observations reveal that the amphiphilic block copolymers aggregate and rearrange to form a micelle with a hydrophobic and rigid core, surrounded by a corona of hydrophilic blocks that extend into the solution. These micelles are stable against coalescence, and once mature, they do not merge. We also show that the encapsulation of hydrophobic NPs is a self-limiting process, which occurs through gradual adsorption of block copolymers; the growth of a polymeric shell around the NPs, shielding them from water, ceases when the NPs are fully covered by the adsorbed copolymers. The insights from these observations are of fundamental importance for the design of biocompatible soft materials.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Micelas , Nanopartículas/química , Adsorção , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Nanomedicina , Polímeros/química , Solventes , Água/química
19.
J Am Chem Soc ; 141(1): 363-369, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30532955

RESUMO

The ensemble of native, folded state was once considered to represent the global energy minimum of a given protein sequence. More recently, the discovery of the cross-ß amyloid state revealed that deeper energy minima exist, often associated with pathogenic, fibrillar deposits, when the concentration of proteins reaches a critical value. Fortunately, a sizable energy barrier impedes the conversion from native to pathogenic states. However, little is known about the structure of the related transition state. In addition, there are indications of polymorphism in the amyloidogenic process. Here, we report the first evidence of the conversion of metastable cross-α-helical crystals to thermodynamically stable cross-ß-sheet-like fibrils by a de novo designed heptapeptide. Furthermore, for the first time, we demonstrate at atomic resolution that the flip of a peptide plane from a type I to a type II' turn facilitates transformation to cross-ß structure and assembly of a dry steric zipper. This study establishes the potential of a peptide turn, a common protein secondary structure, to serve as a principal gatekeeper between a native metastable folded state and the amyloid state.

20.
ACS Appl Mater Interfaces ; 10(43): 36711-36720, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30285412

RESUMO

Self-adjusting omniphilic nanocarriers (OPNs) with a multisolvent aptitude were prepared via a Schiff base reaction between chitosan, a natural polysaccharide, and bioactive aldehydes. Experimental studies supported by atomistic molecular dynamics simulations revealed these OPNs can encapsulate insoluble molecular cargo, transport them in aqueous or lipid environments, and deliver them through cross-phase barriers. N-imine dynamic covalent bonds have been incorporated to endow the OPNs with pH responsiveness, also allowing the amplification of their bioactivity, as demonstrated in vitro with the ability to delay fungal proliferation in wheat grains. The reported OPNs hold remarkable potential as biocompatible nanocarriers for the effective delivery of active agents in agriculture, medicine, and cosmetics.


Assuntos
Antifúngicos/química , Portadores de Fármacos/química , Nanopartículas/química , Polissacarídeos/química , Aldeídos/química , Carbono/química , Quitosana/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Iminas/química , Lipídeos/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Espectroscopia de Infravermelho com Transformada de Fourier
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