RESUMO
Per- and polyfluoroalkyl substances (PFAS) pose significant health risks due to their widespread presence in various environmental and biological matrices. However, the molecular-level mechanisms underlying the interactions between PFAS and biological constituents, including proteins, carbohydrates, lipids, and DNA, remain poorly understood. Here, we investigate the interactions between a legacy PFAS, viz. perfluorooctanoic acid (PFOA), and the milk protein ß-lactoglobulin (BLG) obtained using a combination of experimental and computational techniques. Circular dichroism studies reveal that PFOA perturbs the secondary structure of BLG, by driving a dose-dependent loss of α-helicity and alterations in its ß-sheet content. Furthermore, exposure of the protein to PFOA attenuates the on-rate constant for the binding of the hydrophobic probe 8-anilino-1-naphthalene sulfonic acid (ANS), suggesting potential functional impairment of BLG by PFOA. Steered molecular dynamics and umbrella sampling calculations reveal that PFOA binding leads to the formation of an energetically favorable novel binding pocket within the protein, when residues 129-142 are steered to unfold from their initial α-helical structure, wherein a host of intermolecular interactions between PFOA and BLG's residues serve to insert the PFOA into the region between the unfolded helix and beta-sheets. Together, the data provide a novel understanding of the atomic and molecular mechanism(s) by which PFAS modulates structure and function in a globular protein, leading to a beginning of our understanding of altered biological outcomes.
Assuntos
Caprilatos , Fluorocarbonos , Lactoglobulinas , Fluorocarbonos/química , Caprilatos/química , Lactoglobulinas/química , Lactoglobulinas/metabolismo , Sítios de Ligação , Ligação Proteica , Simulação de Dinâmica Molecular , Conformação Proteica em alfa-Hélice , Modelos Moleculares , Dicroísmo CircularRESUMO
In the face of escalating challenges of microbial resistance strains, this study describes the design and synthesis of 5-({1-[(1H-1,2,3-triazol-4-yl)methyl]-1H-indol-3-yl}methylene)thiazolidine-2,4-dione derivatives, which have demonstrated significant antimicrobial properties. Compared with the minimum inhibitory concentrations (MIC) values of ciprofloxacin on the respective strains, compounds 5a, 5d, 5g, 5l, and 5m exhibited potent antibacterial activity with MIC values ranging from 16 to 25 µM. Almost all the synthesized compounds showed lower MIC compared to standards against vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus strains. Additionally, the majority of the synthesized compounds demonstrated remarkable antifungal activity, against Candida albicans and Aspergillus niger, as compared to nystatin, griseofulvin, and fluconazole. Furthermore, the majority of compounds exhibited notable inhibitory effects against the Plasmodium falciparum strain, having IC50 values ranging from 1.31 to 2.79 µM as compared to standard quinine (2.71 µM). Cytotoxicity evaluation of compounds 5a-q on SHSY-5Y cells at up to 100 µg/mL showed no adverse effects. Comparison with control groups highlights their noncytotoxic characteristics. Molecular docking confirmed compound binding to target active sites, with stable protein-ligand complexes displaying drug-like molecules. Molecular dynamics simulations revealed dynamic stability and interactions. Rigorous tests and molecular modeling unveil the effectiveness of the compounds against drug-resistant microbes, providing hope for new antimicrobial compounds with potential safety.
Assuntos
Antimaláricos , Staphylococcus aureus Resistente à Meticilina , Tiazolidinedionas , Antibacterianos/química , Antimaláricos/farmacologia , Triazóis/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Environmental agents such as pesticides, weedicides and herbicides (collectively referred to as pesticides) are associated with the onset and pathogenesis of neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's (AD) diseases. The development of blood-brain barrier (BBB)-penetrating therapeutic candidates to both prevent and treat the aforementioned xenotoxicant-induced neurodegenerative disorders remains an unmet need. Here, we examine whether caffeic-acid based Carbon Quantum Dots (CACQDs) can intervene in pesticide-associated onset and progress of the PD phenotype. Pulse-chase fluorescence analyses revealed that CACQDs intervene in the soluble-to-toxic transformation of the amyloid-forming protein model Hen Egg White Lysozyme (HEWL). The sp2-rich CACQDs also scavenged free radicals, a milestone along the PD trajectory. In-vitro, CACQDs introduced into a human neuroblastoma-derived cell line (SH-SY5Y) demonstrated negligible cytotoxicity up to 5 mg/mL and protected the cell line against oxidative stress-induced neuronal injury induced by the pesticide and potent neurotoxin, paraquat. Our findings suggest that the potentially BBB-penetrating CACQDs derived from caffeic acid hold promise for mitigating neurodegenerative disorders associated with environmental pesticides and xenobiotic neurotoxicants. Importantly, CACQDs sourced from coffee, coupled with their facile synthesis, represent a sustainable, green chemistry platform for generating interventional candidates in neurodegeneration.
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Oxidative protein folding involves the formation of disulfide bonds and the regeneration of native structure (N) from the fully reduced and unfolded protein (R). Oxidative protein folding studies have provided a wealth of information on underlying physico-chemical reactions by which disulfide-bond-containing proteins acquire their catalytically active form. Initially, we review key events underlying oxidative protein folding using bovine pancreatic ribonuclease A (RNase A), bovine pancreatic trypsin inhibitor (BPTI) and hen-egg white lysozyme (HEWL) as model disulfide bond-containing folders and discuss consequential outcomes with regard to their folding trajectories. We re-examine the findings from the same studies to underscore the importance of forming native disulfide bonds and generating a "native-like" structure early on in the oxidative folding pathway. The impact of both these features on the regeneration landscape are highlighted by comparing ideal, albeit hypothetical, regeneration scenarios with those wherein a native-like structure is formed relatively "late" in the RâN trajectory. A special case where the desired characteristics of oxidative folding trajectories can, nevertheless, stall folding is also discussed. The importance of these data from oxidative protein folding studies is projected onto outcomes, including their impact on the regeneration rate, yield, misfolding, misfolded-flux trafficking from the endoplasmic reticulum (ER) to the cytoplasm, and the onset of neurodegenerative disorders.
Assuntos
Dissulfetos/metabolismo , Dobramento de Proteína , Proteínas/química , Proteínas/metabolismo , Animais , Humanos , Cinética , OxirreduçãoRESUMO
While pharmaceutical drugs have revolutionized human life, there are several features that limit their full potential. This review draws attention to some of the obstacles currently facing the use of chemotherapeutic drugs including low solubility, poor bioavailability and high drug dose. Overcoming these issues will further enhance the applicability and potential of current drugs. An emerging technology that is geared towards improving overall therapeutic efficiency resides in drug delivery systems including the use of polymeric nanoparticles which have found widespread use in cancer therapeutics. These polymeric nanoparticles can provide targeted drug delivery, increase the circulation time in the body, reduce the therapeutic indices with minimal side-effects, and accumulate in cells without activating the mononuclear phagocyte system (MPS). Given the inroads made in the field of nanodelivery systems for pharmaceutical applications, it is of interest to review and emphasize the importance of Polymeric nanocarrier system for drug delivery in chemotherapy.
Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos , Nanopartículas , Polímeros , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Materiais Biocompatíveis/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/química , Nanoestruturas/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Polimerização , Polímeros/síntese química , Polímeros/química , SolventesRESUMO
The practice of medicine is ever evolving. Diagnosing disease, which is often the first step in a cure, has seen a sea change from the discerning hands of the neighborhood physician to the use of sophisticated machines to use of information gleaned from biomarkers obtained by the most minimally invasive of means. The last 100 or so years have borne witness to the enormous success story of allopathy, a practice that found favor over earlier practices of medical purgatory and homeopathy. Nevertheless, failures of this approach coupled with the omics and bioinformatics revolution spurred precision medicine, a platform wherein the molecular profile of an individual patient drives the selection of therapy. Indeed, precision medicine-based therapies that first found their place in oncology are rapidly finding uses in autoimmune, renal and other diseases. More recently a new renaissance that is shaping everyday life is making its way into healthcare. Drug discovery and medicine that started with Ayurveda in India are now benefiting from an altogether different artificial intelligence (AI)-one which is automating the invention of new chemical entities and the mining of large databases in health-privacy-protected vaults. Indeed, disciplines as diverse as language, neurophysiology, chemistry, toxicology, biostatistics, medicine and computing have come together to harness algorithms based on transfer learning and recurrent neural networks to design novel drug candidates, a priori inform on their safety, metabolism and clearance, and engineer their delivery but only on demand, all the while cataloging and comparing omics signatures across traditionally classified diseases to enable basket treatment strategies. This review highlights inroads made and being made in directed-drug design and molecular therapy.
Assuntos
Aprendizado Profundo , Descoberta de Drogas , Medicina de Precisão , Inteligência Artificial , Desenho de Fármacos , Reposicionamento de Medicamentos , Redes Neurais de Computação , Sistemas Automatizados de Assistência Junto ao LeitoRESUMO
The folding of disulfide bond containing proteins proceeds in a biphasic manner. Initially, cysteines are oxidized to form disulfide bonds. Structure is largely absent during this phase. Next, when a minimally correct number of native linkages of disulfide bonds have been acquired, the biopolymer conformationally folds into the native, or a native-like, state. Thus, at the end of this "oxidative folding" process, a stable and biologically active protein is formed. This review focuses on dissecting the "structure-forming step" in oxidative protein folding. The ability to follow this pivotal step in protein maturation in somewhat detail is uniquely facilitated in "oxidative" folding scenarios. We review this step using bovine pancreatic Ribonuclease A as a model while recognizing the impact that this step has in subcellular trafficking and protein aggregation.
Assuntos
Retículo Endoplasmático/metabolismo , Dobramento de Proteína , Ribonuclease Pancreático/metabolismo , Animais , Bovinos , Modelos Moleculares , Oxirredução , Agregados Proteicos , Estrutura Terciária de Proteína , Transporte Proteico , Ribonuclease Pancreático/química , Relação Estrutura-AtividadeRESUMO
Halogen bonding has emerged at the forefront of advances in improving ligand: receptor interactions. In particular the newfound ability of this extant non-covalent-bonding phenomena has revolutionized computational approaches to drug discovery while simultaneously reenergizing synthetic approaches to the field. Here we survey, via examples of classical applications involving halogen atoms in pharmaceutical compounds and their biological hosts, the unique advantages that halogen atoms offer as both Lewis acids and Lewis bases.
Assuntos
Descoberta de Drogas , Halogênios/química , Animais , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Humanos , Ligantes , Modelos Moleculares , Ácidos Nucleicos/química , Proteínas/química , Relação Quantitativa Estrutura-AtividadeRESUMO
Sulfur bonding interactions between organosulfur compounds and proteins were examined using crystal structures deposited to-date in the PDB. The data was analyzed as a function of sulfur-σ-hole-bonding (i.e., sulfur bonds) to main chain Lewis bases, viz. oxygen and nitrogen atoms of the backbone amide linkages. The analyses also included an examination of sulfur bonding to side chain Lewis bases (O, N, and S) and to the "non-classical" Lewis bases present in electron-rich aromatic amino acids as-well-as to donor-acceptor bond angle distributions. The interactions analyzed included those restricted to the sum of van der Waals radii of the respective atoms or to a distance of 4 Å. The surveyed data revealed that sulfur bonding tendencies (C-S-C bond angles) were impacted not only by steric effects but perhaps also by enthalpic features present in both the donor and acceptor participants. This knowledge is not only of fundamental interest but is also important in terms of materials and drug-design involving moieties incorporating the sulfur atom. Additionally, a new empirical scoring function was developed to address the anisotropy of sulfur in protein-ligand interactions. This newly developed scoring function is incorporated into AutoDock Vina molecular docking program and is valuable for modeling and drug design.
Assuntos
Desenho de Fármacos , Simulação de Acoplamento Molecular , Proteínas/metabolismo , Compostos de Enxofre/química , Compostos de Enxofre/farmacologia , Algoritmos , Bactérias/enzimologia , Proteínas de Bactérias/metabolismo , Bases de Dados de Proteínas , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/farmacologia , Ligantes , Plasmodium falciparum/enzimologia , Eletricidade Estática , Enxofre/química , Enxofre/farmacologia , TermodinâmicaRESUMO
We describe a new health care campus under development in the Cayman Islands, Health City, based on the low-cost "focused factory" model. The construction of a multispecialty hospital opening in February 2014 less than a 4-hour flight away from the United States and convenient to both Central and South America for patients who already travel to the United States for clinical care could reshape the US health care marketplace and enhance access to affordable specialty health care in the region.
Assuntos
Atenção à Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/organização & administração , Doenças Cardiovasculares/terapia , Humanos , Internacionalidade , Índias OcidentaisRESUMO
Carbon nanomaterials (CNMs), including carbon quantum dots (CQDs), have found widespread use in biomedical research due to their low toxicity, chemical tunability, and tailored applications. Yet, there exists a gap in our understanding of the molecular interactions between biomacromolecules and these novel carbon-centered platforms. Using gelatin-derived CQDs as a model CNM, we have examined the impact of this exemplar nanomaterial on apo-myoglobin (apo-Mb), an oxygen-storage protein. Intrinsic fluorescence measurements revealed that the CQDs induced conformational changes in the tertiary structure of native, partially unfolded, and unfolded states of apo-Mb. Titration with CQDs also resulted in significant changes in the secondary structural elements in both native (holo) and apo-Mb, as evidenced by the circular dichroism (CD) analyses. These changes suggested a transition from isolated helices to coiled-coils during the loss of the helical structure of the apo-protein. Infra-red spectroscopic data further underscored the interactions between the CQDs and the amide backbone of apo-myoglobin. Importantly, the CQDs-driven structural perturbations resulted in compromised heme binding to apo-myoglobin and, therefore, potentially can attenuate oxygen storage and diffusion. However, a cytotoxicity assay demonstrated the continued viability of neuroblastoma cells exposed to these carbon nanomaterials. These results, for the first time, provide a molecular roadmap of the interplay between carbon-based nanomaterial frameworks and biomacromolecules.
Assuntos
Carbono , Pontos Quânticos , Carbono/química , Mioglobina/química , Gelatina , Pontos Quânticos/química , OxigênioRESUMO
Disorders of the central nervous system (CNS) which include a wide range of neurodegenerative and neurological conditions have become a serious global issue. The presence of CNS barriers poses a significant challenge to the progress of designing effective therapeutic delivery systems, limiting the effectiveness of drugs, genes, and other therapeutic agents. Natural nanocarriers present in biological systems have inspired researchers to design unique delivery systems through biomimicry. As natural resource derived delivery systems are more biocompatible, current research has been focused on the development of delivery systems inspired by bacteria, viruses, fungi, and mammalian cells. Despite their structural potential and extensive physiological function, making them an excellent choice for biomaterial engineering, the delivery of nucleic acids remains challenging due to their instability in biological systems. Similarly, the efficient delivery of genetic material within the tissues of interest remains a hurdle due to a lack of selectivity and targeting ability. Considering that gene therapies are the holy grail for intervention in diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's Disease, and Huntington's disease, this review centers around recent advances in bioinspired approaches to gene delivery for the prevention of CNS disorders.
Assuntos
Materiais Biocompatíveis , Técnicas de Transferência de Genes , Humanos , Materiais Biocompatíveis/química , Animais , Sistema Nervoso Central/metabolismo , Doenças Neurodegenerativas/terapia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Terapia Genética , Doenças do Sistema Nervoso Central/terapia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Tamanho da Partícula , Teste de MateriaisRESUMO
The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aß), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others is associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. The dissolution of mature fibrils and toxic amyloidogenic intermediates including oligomers continues to be the pinnacle in the treatment of neurodegenerative disorders. Yet, methods to effectively, and quantitatively, report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. Here we describe a simplified method that implements the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique implements an optimized but well-known, simple, inexpensive and quantitative assessment previously used to assess the oligomerization of amyloid monomers and subsequent amyloid fibrils. This method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers, dimers, and trimers and/or retain amyloid proteins in their monomeric forms. Most importantly, our optimized method diminishes existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.
RESUMO
The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aß), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others are associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. The dissolution of mature fibrils and toxic amyloidogenic intermediates, including oligomers, continues to be the pinnacle in the treatment of neurodegenerative disorders. Yet, methods to effectively and quantitatively report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. Here we describe a simplified method that implements the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique implements an optimized but well-known, simple, inexpensive, and quantitative assessment previously used to assess the oligomerization of amyloid monomers and subsequent amyloid fibrils. This method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers, dimers, and trimers and/or retain amyloid proteins in their monomeric forms. Most importantly, our optimized method diminishes existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.
Assuntos
Carbono , Humanos , Carbono/química , Agregados Proteicos , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Amiloide/química , Amiloide/metabolismoRESUMO
Micro- and nano-plastics (NPs) are found in human milk, blood, tissues, and organs and associate with aberrant health outcomes including inflammation, genotoxicity, developmental disorders, onset of chronic diseases, and autoimmune disorders. Yet, interfacial interactions between plastics and biomolecular systems remain underexplored. Here, we have examined experimentally, in vitro, in vivo, and by computation, the impact of polystyrene (PS) NPs on a host of biomolecular systems and assemblies. Our results reveal that PS NPs essentially abolished the helix-content of the milk protein ß-lactoglobulin (BLG) in a dose-dependent manner. Helix loss is corelated with the near stoichiometric formation of ß-sheet elements in the protein. Structural alterations in BLG are also likely responsible for the nanoparticle-dependent attrition in binding affinity and weaker on-rate constant of retinol, its physiological ligand (compromising its nutritional role). PS NP-driven helix-to-sheet conversion was also observed in the amyloid-forming trajectory of hen egg-white lysozyme (accelerated fibril formation and reduced helical content in fibrils). Caenorhabditis elegans exposed to PS NPs exhibited a decrease in the fluorescence of green fluorescent protein-tagged dopaminergic neurons and locomotory deficits (akin to the neurotoxin paraquat exposure). Finally, in silico analyses revealed that the most favorable PS/BLG docking score and binding energies corresponded to a pose near the hydrophobic ligand binding pocket (calyx) of the protein where the NP fragment was found to make nonpolar contacts with side-chain residues via the hydrophobic effect and van der Waals forces, compromising side chain/retinol contacts. Binding energetics indicate that PS/BLG interactions destabilize the binding of retinol to the protein and can potentially displace retinol from the calyx region of BLG, thereby impairing its biological function. Collectively, the experimental and high-resolution in silico data provide new insights into the mechanism(s) by which PS NPs corrupt the bimolecular structure and function, induce amyloidosis and onset neuronal injury, and drive aberrant physiological and behavioral outcomes.
Assuntos
Caenorhabditis elegans , Lactoglobulinas , Muramidase , Animais , Muramidase/química , Muramidase/metabolismo , Lactoglobulinas/química , Lactoglobulinas/metabolismo , Caenorhabditis elegans/metabolismo , Poliestirenos/química , Nanopartículas/química , Vitamina A/química , Vitamina A/metabolismo , Humanos , Homeostase/efeitos dos fármacos , Plásticos/químicaRESUMO
Over the last decades, ionic liquids (IL) have shown great potential in non-invasive delivery starting from synthetic small molecules to biological large molecules. ILs are emerging as a particular class of drug delivery systems due to their unique physiochemical properties, simple surface modification, and functionalization. These features of IL help achieve specific design principles that are essential for a non-invasive drug delivery system. In this review, we have discussed IL and their applications in non-invasive drug delivery systems. We evaluated state-of-the-art development and advances of IL aiming to mitigate the biological and physical barriers to improve transdermal and oral delivery, summarized in this review. We also provided an overview of the various factors determining the systemic transportation of IL-based formulation. Additionally, we have emphasized how the ILs facilitate the transportation of therapeutic molecules by overcoming biological barriers.
Assuntos
Líquidos Iônicos , Humanos , Líquidos Iônicos/química , Sistemas de Liberação de Medicamentos , Administração CutâneaRESUMO
Carbon dots (CDs) are carbon nano materials (CNMs) that find use across several biological applications because of their water solubility, biocompatible nature, eco-friendliness, and ease of synthesis. Additionally, their physiochemical properties can be chemically tuned for further optimization towards specific applications. Here, we investigate the efficacy of C70-derived Graphene Acid Quantum Dots (GAQDs) in mitigating the transformation of soluble, monomeric Hen Egg-White Lysozyme (HEWL) to mature fibrils during its amyloidogenic trajectory. Our findings reveal that GAQDs exhibit dose-dependent inhibition of HEWL fibril formation (up to 70 % at 5 mg/mL) without affecting mitochondrial membrane potential or inducing apoptosis at the same density. Furthermore, GAQDs scavenged reactive oxygen species (ROS); achieving a 50 % reduction in ROS levels at a mere 100 µg/mL when exposed to a standard free radical generator. GAQDs were not only found to be biocompatible with a human neuroblastoma-derived SHSY-5Y cell line but also rescued the cells from rotenone-induced apoptosis. The GAQD-tolerance of SHSY-5Y cells coupled with their ability to restitute cells from rotenone-dependent apoptosis, when taken in conjunction with the biocompatibility data, indicate that GAQDs possess neuroprotective potential. The data position this class of CNMs as promising candidates for resolving aberrant cellular outputs that associate with the advent and progress of multifactorial neurodegenerative disorders including Parkinson's (PD) and Alzheimer's diseases (AD) wherein environmental causes are implicated (95 % etiology). The data suggest that GAQDs are a multifunctional carbon-based sustainable nano-platform at the intersection of nanotechnology and neuroprotection for advancing green chemistry-derived, sustainable healthcare solutions.
Assuntos
Apoptose , Grafite , Muramidase , Pontos Quânticos , Espécies Reativas de Oxigênio , Pontos Quânticos/química , Humanos , Grafite/química , Grafite/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Muramidase/química , Muramidase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Animais , Tamanho da Partícula , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Carbono/química , Propriedades de Superfície , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Graphene-based nanomaterials (graphene, graphene oxide, reduced graphene oxide, graphene quantum dots, graphene-based nanocomposites, etc.) are emerging as an extremely important class of nanomaterials primarily because of their unique and advantageous physical, chemical, biological, and optoelectronic aspects. These features have resulted in uses across diverse areas of scientific research. Among all other applications, they are found to be particularly useful in designing highly sensitive biosensors. Numerous studies have established their efficacy in sensing pathogens and other biomolecules allowing for the rapid diagnosis of various diseases. Considering the growing importance and popularity of graphene-based materials for biosensing applications, this review aims to provide the readers with a summary of the recent progress in the concerned domain and highlights the challenges associated with the synthesis and application of these multifunctional materials.
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Halogen bonding interactions between halogenated ligands and proteins were examined using the crystal structures deposited to date in the PDB. The data was analyzed as a function of halogen bonding to main chain Lewis bases, viz. oxygen of backbone carbonyl and backbone amide nitrogen. This analysis also examined halogen bonding to side-chain Lewis bases (O, N, and S) and to the electron-rich aromatic amino acids. All interactions were restricted to van der Waals radii with respective atoms. The data reveals that while fluorine and chlorine have strong tendencies favoring interactions with the backbone Lewis bases at glycine, the trend is not restricted to the achiral amino acid backbone for larger halogens. Halogen side-chain interactions are not restricted to amino acids containing O, N, and S as Lewis bases. Electron-rich aromatic amino acids host a high frequency of halogen bonds as does Leu. A closer examination of the latter hydrophobic side chain reveals that the "propensity of interactions" of halogen ligands at this oily residue is an outcome of strong classical halogen bonds with Lewis bases in the vicinity. Finally, an examination of Θ1 (C-X···O and C-X···N) and Θ2 (X···O-Z and X···N-Z) angles reveals that very few ligands adopt classical halogen bonding angles, suggesting that steric and other factors may influence these angles. The data is discussed in the context of ligand design for pharmaceutical applications.
Assuntos
Aminoácidos/química , Elétrons , Bases de Lewis/química , Proteínas/química , Bases de Dados de Proteínas , Desenho de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Ligantes , Nitrogênio/química , Oxigênio/química , Enxofre/química , TermodinâmicaRESUMO
The soluble-to-toxic transformation of intrinsically disordered amyloidogenic proteins such as amyloid beta (Aß), α-synuclein, mutant Huntingtin Protein (mHTT) and islet amyloid polypeptide (IAPP) among others is associated with disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Type 2 Diabetes (T2D), respectively. Conversely, the dissolution of mature fibrils and toxic amyloidogenic intermediates including oligomers remains the holy grail in the treatment of neurodegenerative disorders. Yet, methods to effectively, and quantitatively, report on the interconversion between amyloid monomers, oligomers and mature fibrils fall short. For the first time, we describe the use of gel electrophoresis to address the transformation between soluble monomeric amyloid proteins and mature amyloid fibrils. The technique permits rapid, inexpensive and quantitative assessment of the fraction of amyloid monomers that form intermediates and mature fibrils. In addition, the method facilitates the screening of small molecules that disintegrate oligomers and fibrils into monomers or retain amyloid proteins in their monomeric forms. Importantly, our methodological advance diminishes major existing barriers associated with existing (alternative) techniques to evaluate fibril formation and intervention.