944 resultados para DRUG TARGETS


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The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer-drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications.

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In recent years, there have been major developments in the understanding of the cell cycle. It is now known that normal cellular proliferation is tightly regulated by the activation and deactivation of a series of proteins that constitute the cell cycle machinery. The expression and activity of components of the cell cycle can be altered during the development of a variety of diseases where aberrant proliferation contributes to the pathology of the illness. Apart from yielding a new source of untapped therapeutic targets, it is likely that manipulating the activity of such proteins in diseased states will provide an important route for treating proliferative disorders, and the opportunity to develop a novel class of future medicines.

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A great explanatory gap lies between the molecular pharmacology of psychoactive agents and the neurophysiological changes they induce, as recorded by neuroimaging modalities. Causally relating the cellular actions of psychoactive compounds to their influence on population activity is experimentally challenging. Recent developments in the dynamical modelling of neural tissue have attempted to span this explanatory gap between microscopic targets and their macroscopic neurophysiological effects via a range of biologically plausible dynamical models of cortical tissue. Such theoretical models allow exploration of neural dynamics, in particular their modification by drug action. The ability to theoretically bridge scales is due to a biologically plausible averaging of cortical tissue properties. In the resulting macroscopic neural field, individual neurons need not be explicitly represented (as in neural networks). The following paper aims to provide a non-technical introduction to the mean field population modelling of drug action and its recent successes in modelling anaesthesia.

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Structural characterization of enzymes that belong to microbial metabolic pathways is very important for structure-based drug design since some of these proteins may be present in the bacterial genome, but absent in humans. Thus, metabolic pathways became potential targets for drug design. The motivation of this work is the fact that Mycobacterium tuberculosis is the cause of the deaths of millions of people in the world, so that the structural characterization of protein targets to propose new drugs has become essential. DBMODELING is a relational database, created to highlight the importance of methods of molecular modeling applied to the Mycobacterium tuberculosis genome with the aim of proposing protein-ligand docking analysis. There are currently more than 300 models for proteins from Mycobacterium tuberculosis genome in the database. The database contains a detailed description of the reaction catalyzed by each enzyme and their atomic coordinates. Information about structures, a tool for animated gif image, a table with a specification of the metabolic pathway, modeled protein, inputs used in modeling, and analysis methods used in this project are available in the database for download. The search tool can be used for reseachers to find specific pathways or enzymes.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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Genome sequencing efforts are providing us with complete genetic blueprints for hundreds of organisms. We are now faced with assigning, understanding, and modifying the functions of proteins encoded by these genomes. DBMODELING is a relational database of annotated comparative protein structure models and their metabolic pathway characterization, when identified. This procedure was applied to complete genomes such as Mycobacteritum tuberculosis and Xylella fastidiosa. The main interest in the study of metabolic pathways is that some of these pathways are not present in humans, which makes them selective targets for drug design, decreasing the impact of drugs in humans. In the database, there are currently 1116 proteins from two genomes. It can be accessed by any researcher at http://www.biocristalografia.df.ibilce.unesp.br/tools/. This project confirms that homology modeling is a useful tool in structural bioinformatics and that it can be very valuable in annotating genome sequence information, contributing to structural and functional genomics, and analyzing protein-ligand docking.

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Background: Uterine Leiomyomas (ULs) are the most common benign tumours affecting women of reproductive age. ULs represent a major problem in public health, as they are the main indication for hysterectomy. Approximately 40-50% of ULs have non-random cytogenetic abnormalities, and half of ULs may have copy number alterations (CNAs). Gene expression microarrays studies have demonstrated that cell proliferation genes act in response to growth factors and steroids. However, only a few genes mapping to CNAs regions were found to be associated with ULs. Methodology: We applied an integrative analysis using genomic and transcriptomic data to identify the pathways and molecular markers associated with ULs. Fifty-one fresh frozen specimens were evaluated by array CGH (JISTIC) and gene expression microarrays (SAM). The CONEXIC algorithm was applied to integrate the data. Principal Findings: The integrated analysis identified the top 30 significant genes (P<0.01), which comprised genes associated with cancer, whereas the protein-protein interaction analysis indicated a strong association between FANCA and BRCA1. Functional in silico analysis revealed target molecules for drugs involved in cell proliferation, including FGFR1 and IGFBP5. Transcriptional and protein analyses showed that FGFR1 (P = 0.006 and P<0.01, respectively) and IGFBP5 (P = 0.0002 and P = 0.006, respectively) were up-regulated in the tumours when compared with the adjacent normal myometrium. Conclusions: The integrative genomic and transcriptomic approach indicated that FGFR1 and IGFBP5 amplification, as well as the consequent up-regulation of the protein products, plays an important role in the aetiology of ULs and thus provides data for potential drug therapies development to target genes associated with cellular proliferation in ULs. © 2013 Cirilo et al.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

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Crotamine, a 42-residue polypeptide derived from the venom of the South American rattlesnake Crotalus durissus terrificus, has been shown to be a cell-penetrating protein that targets chromosomes, carries plasmid DNA into cells, and shows specificity for actively proliferating cells. Given this potential role as a nucleic acid-delivery vector, we have studied in detail the binding of crotamine to single- and double-stranded DNAs of different lengths and base compositions over a range of ionic conditions. Agarose gel electrophoresis and ultraviolet spectrophotometry analysis indicate that complexes of crotamine with long-chain DNAs readily aggregate and precipitate at low ionic strength. This aggregation, which may be important for cellular uptake of DNA, becomes less likely with shorter chain length. 25-mer oligonucleotides do not show any evidence of such aggregation, permitting the determination of affinities and size via fluorescence quenching experiments. The polypeptide binds non-cooperatively to DNA, covering about 5 nucleotide residues when it binds to single (ss) or (ds) double stranded molecules. The affinities of the protein for ss-vs. ds-DNA are comparable, and inversely proportional to salt levels. Analysis of the dependence of affinity on [NaCl] indicates that there are a maximum of,3 ionic interactions between the protein and DNA, with some of the binding affinity attributable to non-ionic interactions. Inspection of the three-dimensional structure of the protein suggests that residues 31 to 35, Arg-Trp-Arg-Trp-Lys, could serve as a potential DNA-binding site. A hexapeptide containing this sequence displayed a lower DNA binding affinity and salt dependence as compared to the full-length protein, likely indicative of a more suitable 3D structure and the presence of accessory binding sites in the native crotamine. Taken together, the data presented here describing crotamine-DNA interactions may lend support to the design of more effective nucleic acid drug delivery vehicles which take advantage of crotamine as a carrier with specificity for actively proliferating cells. Citation: Chen P-C, Hayashi MAF, Oliveira EB, Karpel RL (2012) DNA-Interactive Properties of Crotamine, a Cell-Penetrating Polypeptide and a Potential Drug Carrier. PLoS ONE 7(11): e48913. doi:10.1371/journal.pone.0048913

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The pathophysiology of neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD) has not yet been completely elucidated. However, in the past few years, there have been great knowledge advances about intra-and extracellular proteins that may display impaired function or expression in AD, PD and other ND, such as amyloid beta (AB), alpha-synuclein, tau protein and neuroinfiammatory markers. Recent developments in the imaging techniques of positron emission tomography (PET) and single photon emission computed tomography (SPECT) now allow the non-invasive tracking of such molecular targets of known relevance to ND in vivo. This article summarizes recent findings of PET and SPECT studies using these novel methods, and discusses their potential role in the field of drug development for ND as well as future clinical applications in regard to differential diagnosis of ND and monitoring of disease progression.

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During the previous 10 years, global R&D expenditure in the pharmaceuticals and biotechnology sector has steadily increased, without a corresponding increase in output of new medicines. To address this situation, the biopharmaceutical industry's greatest need is to predict the failures at the earliest possible stage of the drug development process. A major key to reducing failures in drug screenings is the development and use of preclinical models that are more predictive of efficacy and safety in clinical trials. Further, relevant animal models are needed to allow a wider testing of novel hypotheses. Key to this is the developing, refining, and validating of complex animal models that directly link therapeutic targets to the phenotype of disease, allowing earlier prediction of human response to medicines and identification of safety biomarkers. Morehover, well-designed animal studies are essential to bridge the gap between test in cell cultures and people. Zebrafish is emerging, complementary to other models, as a powerful system for cancer studies and drugs discovery. We aim to investigate this research area designing a new preclinical cancer model based on the in vivo imaging of zebrafish embryogenesis. Technological advances in imaging have made it feasible to acquire nondestructive in vivo images of fluorescently labeled structures, such as cell nuclei and membranes, throughout early Zebrafishsh embryogenesis. This In vivo image-based investigation provides measurements for a large number of features at cellular level and events including nuclei movements, cells counting, and mitosis detection, thereby enabling the estimation of more significant parameters such as proliferation rate, highly relevant for investigating anticancer drug effects. In this work, we designed a standardized procedure for accessing drug activity at the cellular level in live zebrafish embryos. The procedure includes methodologies and tools that combine imaging and fully automated measurements of embryonic cell proliferation rate. We achieved proliferation rate estimation through the automatic classification and density measurement of epithelial enveloping layer and deep layer cells. Automatic embryonic cells classification provides the bases to measure the variability of relevant parameters, such as cell density, in different classes of cells and is finalized to the estimation of efficacy and selectivity of anticancer drugs. Through these methodologies we were able to evaluate and to measure in vivo the therapeutic potential and overall toxicity of Dbait and Irinotecan anticancer molecules. Results achieved on these anticancer molecules are presented and discussed; furthermore, extensive accuracy measurements are provided to investigate the robustness of the proposed procedure. Altogether, these observations indicate that zebrafish embryo can be a useful and cost-effective alternative to some mammalian models for the preclinical test of anticancer drugs and it might also provides, in the near future, opportunities to accelerate the process of drug discovery.

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Drug addiction manifests clinically as compulsive drug seeking, and cravings that can persist and recur even after extended periods of abstinence. The fundamental principle that unites addictive drugs is that each one enhances synaptic DA by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. Our attention has focused on the study of phenomena associated with the consumption of alcohol and heroin. Alcohol has long been considered an unspecific pharmacological agent, recent molecular pharmacology studies have shown that acts on different primary targets. Through gene expression studies conducted recently it has been shown that the classical opioid receptors are differently involved in the consumption of ethanol and, furthermore, the system nociceptin / NOP, included in the family of endogenous opioid system, and both appear able to play a key role in the initiation of alcohol use in rodents. What emerges is that manipulation of the opioid system, nociceptin, may be useful in the treatment of addictions and there are several evidences that support the use of this strategy. The linkage between gene expression alterations and epigenetic modulation in PDYN and PNOC promoters following alcohol treatment confirm the possible chromatin remodeling mechanism already proposed for alcoholism. In the second part of present study, we also investigated alterations in signaling molecules directly associated with MAPK pathway in a unique collection of postmortem brains from heroin abusers. The interest was focused on understanding the effects that prolonged exposure of heroin can cause in an individual, over the entire MAPK cascade and consequently on the transcription factor ELK1, which is regulated by this pathway. We have shown that the activation of ERK1/2 resulting in Elk-1 phosphorylation in striatal neurons supporting the hypothesis that prolonged exposure to substance abuse causes a dysregulation of MAPK pathway.

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Tumor is a lesion that may be formed by an abnormal growth of neoplastic cells. Many factors increase the risk of cancer and different targets are involved in tumor progression. Within this thesis, we have addressed two different biological targets, independently connected with tumor formation, e.g. Hsp90 and androgen receptor. The ATP-dependent chaperone Hsp90 is responsible for the conformational maturation and the renaturation of proteins. “Client” proteins are associated with the cancer hallmarks, as cell proliferation and tumor progression. Consequently, Hsp90 has evolved into promising anticancer target. Over the past decade, radicicol has been identified as potential anticancer agent targeting Hsp90, but it is not active in vivo. With that aim of obtaining radicicol-related derivatives, we developed the design and synthesis of new chalcones analogs. Chalcones, which are abundant in edible plants, own a diverse array of pharmacological activities and are considered a versatile scaffold for drug design. Antiproliferative assays and western blot analysis on the new compounds showed that some of those display an interesting cytotoxic effect and the ability to modulate Hsp90 client proteins expression. Androgen Receptor (AR) hypersensitivity plays crucial role in prostate cancer, which progression is stimulated by androgens. The therapy consists in a combination of surgical or chemical castration, along with antiandrogens treatment. Casodex® (bicalutamide), is the most widespread antiandrogen used in clinic. However, hormonal therapy is time-limited since many patients develop resistance. Commercially available antiandrogens show a common scaffold, e.g. two substituted aromatic rings linked by a linear or a cyclic spacer. With the aim of obtaining novel pure AR antagonists, we developed a new synthetic methodology, which allowed us to introduce, as linker between two suitably chosen aromatic rings, a triazole moiety. Preliminary data suggest that the herein reported new molecules generally decrease PSA expression, thus confirming their potential AR antagonistic activity.

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In the past years, genome biology had disclosed an ever-growing kind of biological targets that emerged as ideal points for therapeutic intervention. Nevertheless, the number of new chemical entities (NCEs) translated into effective therapies employed in the clinic, still not observed. Innovative strategies in drug discovery combined with different approaches to drug design should be searched for bridge this gap. In this context organic synthetic chemistry had to provide for effective strategies to achieve biologically active small molecules to consider not only as potentially drug candidates, but also as chemical tools to dissect biological systems. In this scenario, during my PhD, inspired by the Biology-oriented Synthesis approach, a small library of hybrid molecules endowed with privileged scaffolds, able to block cell cycle and to induce apoptosis and cell differentiation, merged with natural-like cores were synthesized. A synthetic platform which joined a Domino Knoevenagel-Diels Alder reaction with a Suzuki coupling was performed in order to reach the hybrid compounds. These molecules can represent either antitumor lead candidates, or valuable chemical tools to study molecular pathways in cancer cells. The biological profile expressed by some of these derivatives showed a well defined antiproliferative activity on leukemia Bcr-Abl expressing K562 cell lines. A parallel project regarded the rational design and synthesis of minimally structurally hERG blockers with the purpose of enhancing the SAR studies of a previously synthesized collection. A Target-Oriented Synthesis approach was applied. Combining conventional and microwave heating, the desired final compounds were achieved in good yields and reaction rates. The preliminary biological results of the compounds, showed a potent blocking activity. The obtained small set of hERG blockers, was able to gain more insight the minimal structural requirements for hERG liability, which is mandatory to investigate in order to reduce the risk of potential side effects of new drug candidates.