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Results for “target validation”

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PubMed2006

Novel targets for tuberculosis drug discovery.

Since the determination of the Mycobacterium tuberculosis genome sequence, various groups have used the genomic information to identify and validate targets as the basis for the development of new anti-tuberculosis agents. Validation might include many components: demonstration of the biochemical activity of the enzyme, determination of its crystal structure in complex with an inhibitor or a substrate, confirmation of essentiality, and the identification of potent growth inhibitors either in vitro or in an infection model. If novel target validation and subsequent inhibition are matched by an improved understanding of disease biology, then new antibiotics could have the potential to shorten the duration of therapy, prevent resistance development and eliminate latent disease.

Amino Acids↗

PubMed2000

The impact of genomics on drug discovery.

High-throughput gene sequencing has revolutionized the process used to identify novel molecular targets for drug discovery. Thousands of new gene sequences have been generated but only a limited number of these can be converted into validated targets likely to be involved in disease. We describe here some of the approaches used at SmithKline Beecham to select and validate novel targets. These include the identification of selective tissue gene product expression, such as for cathepsin K, a novel osteoclast-specific cysteine protease. We also describe the discovery and functional characterization of novel members of the G-protein coupled receptor superfamily and their pairing with natural ligands. Lastly, we discuss the promises of gene microarrays and proteomics, developing technologies that allow the parallel analyses of tissue expression patterns of thousands of genes or proteins, respectively.

Animals↗

PubMed2004

Serum proteomic profiles suggest celecoxib-modulated targets and response predictors.

Cyclooxygenase-2 is a valid target for cancer prevention and treatment. This has been shown in preclinical and clinical cancer prevention studies by using a cyclooxygenase-2 inhibitor, celecoxib. When used in a randomized cancer prevention clinical trial on patients with the inherited autosomal dominant condition, familial adenomatous polyposis, celecoxib proved efficacious. However, a remarkable heterogeneity in patients' responses to the chemopreventive effects of celecoxib was observed. Proteomic profiling of sera from these patients identified several markers, the expression of which was specifically modulated after treatment with celecoxib. A decision tree algorithm identified classifiers for response to celecoxib with relatively high sensitivity but moderate to low specificity. In particular, a spectral feature at m/z 16,961.4 was identified as a strong discriminator between response and nonresponse to celecoxib at the highest dose.

Adenomatous Polyposis Coli↗

PubMed1999

Selective removal of cholinergic neurons in the basal forebrain alters cued target detection.

A spatial orienting task was used to assess attention in rats with selective cholinergic lesions of the basal forebrain. The task required each rat to press a lever in response to a visual target that could occur in one of two locations. A target could be preceded by a cue that either accurately predicted the location of the target (valid) or appeared in the location opposite the target (invalid). Target detection was facilitated by valid cues and degraded by invalid cues in control rats. Performance of rats with lesions was equivalent to that of control rats for valid cues, but reflected an increased cost of invalid cueing. These data support a modulatory role for the basal forebrain cholinergic system in visuospatial attention.

Animals↗

PubMed2004

Expediting target identification and validation through RNAi.

RNA interference (RNAi) is an efficient post-transcriptional gene silencing mechanism that is induced by double-stranded RNA. Applications of RNAi have gained increasing attention since the groundbreaking discovery that small interfering RNA (siRNA) molecules can be used to inhibit gene expression in mammalian cells in a sequence-specific manner. Numerous meetings have recently been held in this field, but the organiser from EF International succeeded in bringing some of the leading academic scientists and company researchers together in London to present and discuss exciting new results. Major topics covered in the meeting included the recent progress in understanding the basic mechanism of RNAi, genome-wide RNAi-based screens for target discovery, and approaches to use RNAi for target validation in cell culture and in animal models. In addition, borders and caveats of the technology, such as off-target effects and a possible induction of the interferon response by siRNA, have been discussed intensively. The use of siRNAs can be regarded as a highly potent strategy to identify and validate new targets for therapeutic interventions against cancer, viral infections, chronic pain and other diseases. Finally, siRNAs themselves hold the promise to become therapeutic agents in the near future.

Animals↗

PubMed2000

Applied genomics: integration of the technology within pharmaceutical research and development.

Multiple novel technologies have recently been developed to improve the analysis of genetic sequences, to rapidly assess RNA or protein levels in relevant tissues, and to validate function of potential new drug targets. The challenge facing pharmaceutical research is one of effective integration of these new technologies in ways that can maximally affect the discovery and development pipeline. Although database mining and transcriptional profiling clearly have increased the number of putative targets, the current focus is to assign function to new gene targets in a high-throughput manner. This requires a restructuring of the classical linear progression from gene identification, functional elucidation, target validation and screen development. New approaches are called for that can make this process non-linear and high-throughput.

Animals↗

PubMed2005

Exploring the sounds of silence: RNAi-mediated gene silencing for target identification and validation.

Drug development begins with the identification and early preclinical validation of novel biological targets, a process often called 'target identification and validation'. This process usually uses various approaches, such as observations from literature and findings from animal or clinical studies, together with cutting edge molecular techniques that include analyses of gene and protein expression, interaction and function. The publication of the human genome has increased research in gene and protein expression analysis that, in combination with RNA interference technology, promises the evaluation of novel functions for known genes, as well as hitherto unknown or unstudied genes with functions relevant to disease.

Drug Design↗

PubMed2001

Fibrosis--a review of recent patent literature.

This review covers recent patent literature for fibrosis for the period 1996 to 2001. Fibrosis related-diseases remain the number one killer in the world, accounting for more than 45% of entire mortality, but there are currently no adequate therapies for most fibrotic conditions. In recent years, however, antifibrotic therapeutics have rapidly progressed following the re-investigation of existing agents that are biologically relevant to the course of fibrosis, the discovery of new targets and the reinstitution of old validated targets. The rapid progress in assay development, recombinant protein production and combinatorial chemistry has allowed more new antifibrotic agents to emerge.

Journal Article↗

PubMed2005

RNAi and high-content screening in target identification and validation.

The development of effective novel therapeutic agents faces many significant challenges, such as demonstrating that a candidate target plays a critical role in disease progression. RNA interference (RNAi) has proven to be a robust and highly scalable technology, and as such, has become an essential method for studying targets in many disease models. High-content screening (HCS) is a platform for quantitatively measuring cellular features such as transcription factor localization. This is a more powerful method of measuring signal transduction than reporter assays because the image-based data of HCS can eliminate many sources of assay artifacts, and the associated statistical tools are highly effective. While it appears obvious that convergence of technologies is required to establish RNAi screening assays in HCS formats, some challenges arise when combining the approaches. However, combining RNAi and HCS provides significant and unique advantages to a target validation program.

Animals↗

PubMed2000

Visuospatial attention and motor reaction in children: an electrophysiological study of the "Posner" paradigm.

To assess the processing stages involved in attention shifting and response selection tasks in children, we recorded event-related potentials (ERPs) and performance measures during a variant of the Posner paradigm. Subjects responded to visual targets, either preceded by a spatial cue (valid = same side; invalid = opposite side) or presented uncued. Valid targets evoked high-amplitude P1 responses, single-peaked P3s, and the shortest reaction times (RTs). Invalidity cued stimuli evoked delayed RTs, resulting in part from incorrectly oriented attention (decreased P1) leading to delayed target processing (belated N2-P3). Invalid targets also evoked a positive slow wave attributed to prolonged response selection due to cue/target incompatibility. Uncued stimuli elicited the longest RTs, unexplained by deficits in target detection or response selection, which likely resulted from a deficit in motor preparation due to the lack of warning signal. This method may be applied in clinical settings to disentangle selective processing deficits in target detection, response selection, or motor preparation stages.

Adolescent↗

PubMed2003

Metformin and its liver targets in the treatment of type 2 diabetes.

Although a number of assessments disagree, the preponderance of the evidence indicates that the major therapeutic action of metformin in type 2 diabetes (DM2) is on the liver, and glucose production (EGP) in particular. At the level of this organ, the actions of metformin can be characterized as pleiotropic. The major questions addressed here are therefore: (i) the methodological aspects of the determination of glucose fluxes: when glucose production is not found to be elevated in type 2 diabetes, it is not surprising that little action of metformin on this flux is found. The issues of populations examined, experimental protocols, and quantitative methods of flux determination are important in answering this question. Early morning EGP is increased and constitutes a valid target for metformin. (ii) the multiple targets of metformin: metformin acts at a number of sites and interacts with metabolites and hormones. Some of these actions may be expressed at different doses. Although their net effect is therapeutic, not all are oriented towards lowering hyperglycemia, perhaps explaining the more modest effect of this drug than could be anticipated from individual actions. Sites of metformin action can therefore be considered as a compilation of valid therapeutic targets in DM2. Gluconeogenesis, glycogenolysis and glycogen synthesis can be altered by metformin, although in vivo, this also depends on the methodology. Component processes from substrate supply and liver uptake, through a number of glucogenic enzymes, as well as glycogen synthase and phosphorylase have all been shown to be affected. (iii) unifying concepts: reported actions of metformin on the mitochondrial respiratory chain, free fatty acid metabolism, AMP-activated protein kinase, and on membrane proteins directly may all explain subsets of actions that are seen, providing more integrated targets for consideration in the therapy of DM2.

Animals↗

PubMed2005

Target identification and validation in drug discovery: the role of proteomics.

Proteomics, the study of cellular protein expression, is an evolving technology platform that has the potential to identify novel proteins involved in key biological processes in the cell that may serve as potential drug targets. While proteomics has considerable theoretical promise, individual cells/tissues have the potential to generate many millions of proteins while the current analytical technologies that involve the use of time-consuming two dimensional gel electrophoresis (2DIGE) and various mass spectrometry (MS) techniques are unable to handle complex biological samples without multiple high-resolution purification steps to reduce their complexity. This can significantly limit the speed of data generation and replication and requires the use of bioinformatic algorithms to reconstitute the parent proteome, a process that does not always result in a reproducible outcome. In addition, membrane bound proteins, e.g., receptors and ion channels, that are the targets of many existing drugs, are not amenable to study due, in part, to limitations in current proteomic techniques and also to these being present in low abundance and thus disproportionally represented in proteome profiles. Subproteomes with reduced complexity have been used to generate data related to specific, hypothesis-driven questions regarding target identification, protein-interaction networks and signaling pathways. However progress to date, with the exception of diagnostic proteomics in the field of cancer, has been exceedingly slow with an inability to put such studies in the context of a larger proteome, limiting the value of the information. Additionally the pathway for target validation (which can be more accurately described at the preclinical level as target confidence building) remains unclear. It is important that the ability to measure and interrogate proteomes matches expectations, avoiding a repetition of the disappointment and subsequent skepticism that accompanied what proved to be unrealistic expectations for the rapid contribution of data based on the genome maps, to biomedical research.

Computational Biology↗

PubMed2005

[Methods of experimental validation of potential target proteins for creation of new drugs].

Review is devoted to the description of the main existing and developing technologies for experimental validation of potential targets predicted in silico by comparative genomics and bioinformatics methods. Since this problem has not been solved yet, the description of a wide set of methods, suitable for the validation of potential targets, is given. The following questions have been considered: (1) applications of proteomic technologies (control of potential targets expression and their variability, analysis of protein-protein interactions); (2) use of genomics technologies in experimental validation of targets (inactivation of the target genes, suppression of transcription, inactivation of the target mRNA, suppression of translation); (3) methods of direct inactivation of target proteins (monoclonal antibodies, light-inactivation, one-chain antibodies, intrabodies, aptamers); (4) high-throughput technologies; (5) targets validations in vivo.

Animals↗

PubMed1999

Disruption, replacement, and cosuppression of nitrate assimilation genes in Stagonospora nodorum.

We used Stagonospora (Septoria) nodorum to explore gene disruption as a general method of fungicide target validation. Nitrate reductase was chosen as a model target because the gene (NIA1) has been cloned from S. nodorum and disruptants should have a readily detectable phenotype (chlorate resistant and nitrate nonutilizing). We have succeeded in disrupting the NIA1 gene by both integration of an unselected vector during cotransformation and one-step gene replacement. Around 2% of transformants from the cotransformation approach became nitrate nonutilizing and Southern analysis confirmed disruption of the resident NIA1 gene. Half of the transformants with the gene replacement vector showed the nitrate nonutilizing phenotype expected from disruption. However, Southern analyses of 14 of these transformants showed that only 6 contained the expected NIA1 gene replacement. Of the remaining transformants, 6 had integrated multiple copies of the vector elsewhere in their genome and still had a functional nitrate reductase gene. Their inability to utilize nitrate was due to a lack of nitrite reductase activity. How this phenotype arose is not clear, but it might involve cosuppression of the nitrite reductase gene as the vector carried 1. 1 kb of the coding region and the complete 5' region of this gene which is adjacent to NIA1. Mutants of both types retained full pathogenicity in detached leaf assays, thereby invalidating both nitrate and nitrite reductase as fungicide targets.

Blotting, Southern↗

PubMed2004

Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery.

Because psychoactive plants exert profound effects on human perception, emotion, and cognition, discovering the molecular mechanisms responsible for psychoactive plant actions will likely yield insights into the molecular underpinnings of human consciousness. Additionally, it is likely that elucidation of the molecular targets responsible for psychoactive drug actions will yield validated targets for CNS drug discovery. This review article focuses on an unbiased, discovery-based approach aimed at uncovering the molecular targets responsible for psychoactive drug actions wherein the main active ingredients of psychoactive plants are screened at the "receptorome" (that portion of the proteome encoding receptors). An overview of the receptorome is given and various in silico, public-domain resources are described. Newly developed tools for the in silico mining of data derived from the National Institute of Mental Health Psychoactive Drug Screening Program's (NIMH-PDSP) K(i) Database (K(i) DB) are described in detail. Additionally, three case studies aimed at discovering the molecular targets responsible for Hypericum perforatum, Salvia divinorum, and Ephedra sinica actions are presented. Finally, recommendations are made for future studies.

Animals↗

PubMedDate not supplied

Cardiovascular prevention in type 2 diabetic patients: review of efficacious treatments.

BACKGROUND: Type 2 diabetes (t2DM) is a chronic and complex metabolic condition requiring continuing medical care in order to reduce the risk of long-term complications. Macrovascular complications cause about 65% of deaths in subjects with t2DM and are responsible for severe co-morbidity. Many studies have addressed cardiovascular (CV) risk reduction in t2DM subjects. OBJECTIVES: To summarise the evidence concerning the impact of lifestyle and of medical interventions in t2DM patients on CV risk (myocardial infarction, stroke, CV death, or a combination of these). METHODS: We successively reviewed the recent guidelines addressing CV prevention in t2DM and searched the Cochrane Controlled Trials Register (CCTR), Medline & Embase to find systematic reviews and original articles on CV events in t2DM patients. We selected original studies which included solely t2DM patients or a large t2DM subgroup (n>100), tested lifestyle habits or drug treatments, and analysed CV endpoints. Their design had to be a randomised controlled trial for drug interventions, and a prospective cohort for lifestyle habits. MAIN STUDIES: We found 4 major guidelines focusing on CV prevention in t2DM patients, all released in 2003, and 10 reviews and meta-analyses: one dealing with dietary intervention, three with blood pressure lowering, one with ACE-inhibitors, one (with update) with platelet-inhibitors , three with cholesterol-inhibitors and one that dealt with both cholesterol-inhibition and blood pressure lowering. We included cohort studies on cigarette smoking (1), physical exercise (3) and weight control (1), as well as randomised trials on treatment of glycaemia (1), lipidaemia (13), blood pressure (12) and platelet aggregation (4). We also included one open randomised trial dealing with a multifactorial treatment. CONCLUSIONS: Global CV risk management in t2DM should aim at changes in lifestyle habits and daily use of multiple drugs. Treatment should be long-term and target-driven with intensified interventions aimed at all validated targets. Lifestyle approach is of primary importance. Five targets are supported by strong clinical evidence (Table 4): reduction of blood pressure and of LDL-Cholesterol to normal values, and the use of three types of drugs which inhibit, respectively, platelet aggregation, angiotensin pathway and cholesterol synthesis.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Exploitation of silicon medicinal chemistry in drug discovery.

There remains considerable pressure on the pharmaceutical industry to increase productivity and reduce the attrition of drug candidates. Genomics, parallel chemistry and high-throughput biology have not yielded the anticipated benefits, resulting in a renewed focus on validated targets and an aim to generate drugs directed towards such targets, which have a clear advantage. One strategy to identify and develop best-in-class drugs is to apply a high degree of innovation in chemistry and apply this to targets from gene families that have been clinically validated as tractable and drugable. The application of organosilicon medicinal chemistry in the context of privileged structures to aid drug design and development is one such innovative approach that is reviewed in this paper.

Animals↗

PubMed2001

Unexploited viral and host targets for the treatment of human immunodeficiency virus type 1 infection.

To date, all approved drugs for the treatment of infection by human immunodeficiency virus type 1 (HIV-1) target either of two viral enzymes, reverse transcriptase or protease. Drugs targeting different macromolecules could improve upon current shortcomings (ex, drug resistance, metabolism, toxicity, formulation) and provide foundations for novel combination therapies. This review will focus on the two key challenges for any new target--target validation (demonstrating the role in the disease), and target tractability (the likelihood of identifying modulators of that target that have drug-like properties). For this discussion, drug-like molecules are orally active, relatively small organic molecules. All of the virally-encoded proteins (other than reverse transcriptase and protease) and the host targets that have been postulated to be critical for HIV-1 proliferation will be reviewed.

Acquired Immunodeficiency Syndrome↗