Drug Discovery Today

Adverse insults during intrauterine life can result in permanent changes in the physiology and metabolism of the offspring, which in turn leads to an increased risk of disease in adulthood. This is an adaptational response by the fetus to changes in the environmental signals that it receives during early life to ensure its survival and prepare itself for postnatal life. Increasing evidence suggests that the epigenetic regulation of gene expression patterns has a crucial role in the developmental programming of adult disease. This review summarizes recent studies of epigenetic mechanisms and focuses particularly on studies that explore identifiable epigenetic biomarkers in the promoters of specific disease-associated genes. Such biomarkers would enable early recognition of children who might be at risk of developing adult disease with fetal origins.

Lyotropic liquid crystal systems, such as reversed bicontinuous cubic and hexagonal mesophases, are attracting more and more attention because of their unique microstructures and physicochemical properties. Various bioactive molecules such as chemical drugs, peptides and proteins can be solubilized in either aqueous or oil phase and be protected from hydrolysis or oxidation. Furthermore, several studies have demonstrated sustained release of bioactive molecules from reversed cubic and hexagonal mesophases. This article gives an overview of recent advances and current status of reversed cubic and hexagonal mesophases, especially with respect to their preparation methods and applications in the field of drug delivery. In addition, potential problems and possible future research directions are highlighted.

The management of traumatic brain injury (TBI) is challenging and there is a need for neuroprotective therapies. A better understanding of the pathomechanism of TBI, particularly of the evolution of secondary damage, is providing targets for new approaches and selected ones in clinical development are described. Clinical trials that have been discontinued in the past for lack of efficacy or other reasons are also listed. One of the problems has been the translation of promising animal experimental results into clinically successful therapies. The complexity of sequelae of TBI requires a multifaceted approach. In addition to the investigation of drugs for neuroprotective effect in TBI, new technologies based on cell/gene therapies, biomarkers and nanobiotechnology are being employed for the integration of neuroprotection with neuroregeneration and are promising.

Absorption, distribution, metabolism and excretion (ADME) studies, are widely used in drug discovery to optimize the balance of properties necessary to convert leads into good medicines. However, throughput using traditional methods is now too low to support recent developments in combinatorial and library chemistry, which have generated many more molecules of interest. To the more enlightened practitioners of ADME science, this situation is generating both the problem and the solution: an opportunity is now forming, with the use of higher throughput ADME screens and computational models, to access this wide chemical diversity and to dissect out the rules that dictate a pharmacokinetic or metabolic profile. In the future we could see ADME properties designed-in from the first principles in drug design.

RNA interference (RNAi) has revolutionized the study of biology and offers numerous applications in basic biology as well as in drug discovery research. Since the discovery of RNAi, several tools have been developed to enable loss-of-function studies in mammalian systems. The efficacy of RNAi is dependent on specific and versatile RNAi triggers that have evolved to enable transient, stable and in-vivo applications. Recently developed genome-wide short hairpin RNA (shRNA) and microRNA-adapted short hairpin RNA (shRNAmir) libraries incorporate advances in shRNA design and molecular 'barcodes' to enable more complex RNAi screens and the opportunity to progress to more complex genetics in whole animals.

Several cytokines have been investigated in clinical trials, based on their potent therapeutic activity observed in animal models of cancer and other diseases. However, substantial toxicities are often reported at low doses, thus preventing escalation to therapeutically active regimens. The use of recombinant antibodies or antibody fragments as delivery vehicles promises to enhance greatly the therapeutic index of pro-inflammatory and anti-inflammatory cytokines. This review surveys preclinical and clinical data published in the field of antibody-cytokine fusions (immunocytokines). Molecular determinants (such as molecular format, valence, target antigen), which crucially contribute to immunocytokine performance in vivo, are discussed in the article, as well as recent trends for the combined use of this novel class of biopharmaceuticals with other therapeutic agents.

Peptide aptamers are combinatorial protein reagents that bind to target proteins with a high specificity and a strong affinity. By so doing, they can modulate the function of their cognate targets. Because peptide aptamers introduce perturbations that are similar to those caused by therapeutic molecules, their use identifies and/or validates therapeutic targets with a higher confidence level than is typically provided by methods that act upon protein expression levels. The unbiased combinatorial nature of peptide aptamers enables them to 'decorate' numerous polymorphic protein surfaces, whose biological relevance can be inferred through characterization of the peptide aptamers. Bioactive aptamers that bind druggable surfaces can be used in displacement screening assays to identify small-molecule hits to the surfaces. The peptide aptamer technology has a positive impact on drug discovery by addressing major causes of failure and by offering a seamless, cost-effective process from target validation to hit identification.

Current developments in basic discovery sciences have not been mirrored by the same level of progress in understanding the clinical basis of disease and ultimately the development of novel effective therapies. This can be improved by applying translational research throughout the late-stage discovery and exploratory development stages of drug development. A bi-directional dialogue between research scientists and clinicians concerning the biology of mechanism of action and clinical basis for disease will deliver biomarkers that enable drug development decisions to be made earlier and with increased confidence. Thus, we can better exploit the many targets that have been discovered through the mapping of the genome and other breakthroughs in medical sciences, such as the polyomic technologies.

At the single-cell level in conjunction with data-pattern analysis, high-content screening by image analysis or flow cytometry of clinical cell- or tissue-section samples provides differential molecular profiles for the personalized prediction of therapy-dependent disease progression in patients. The molecular reverse-engineering of these molecular profiles, which is the exploration of molecular pathways, backwards, to the origin of the observed molecular differentials, by systems biology has the potential to detect new drug targets in knowledge spaces, typically inaccessible to traditional hypotheses. Furthermore, predictive medicine, by cytomics in stratified patient groups, opens a new way for personalized (or individualized) medicine, as well as for the early detection of adverse drug reactions in patients.

'A wise use of lead discovery tactics will distinguish successful drug discovery engines.'

The use of RNA interference (RNAi) is spreading rapidly to nearly every aspect of biomedical research. The gene silencing capability of RNAi is being used to study individual gene's biological function and role in biochemical pathways. However, the efficacy of RNAi depends upon efficient delivery of the intermediates of RNAi, short interfering RNA (siRNA) and short hairpin RNA (shRNA) oligonucleotides. The delivery challenge is even greater when the aim is to inhibit the expression of target genes in animal models. Although i n vivo delivery of siRNA is complicated and challenging, recent results are encouraging. In this review, the latest developments of in vivo delivery of siRNA and the crucial issues related to this effort are addressed.

T-cell-epitope mapping has emerged as one of the most powerful new drug discovery tools for a range of biomedical applications. Initially, T-cell-epitope discovery was applied to the development of vaccines for infectious diseases and cancer. T-cell-epitope-mapping applications have now expanded to include reengineering of protein therapeutics (a process now called deimmunization), as well as the fields of autoimmunity, endocrinology, allergy, transplantation and diagnostics. Research employing T-cell-epitope mapping falls within the realm of immunomics, a new field that addresses the interface between host and (pathogen) proteome, bridging informatics, genomics, proteomics, immunology and clinical medicine. This review highlights aspects of recent immunomics research that are related to the discovery of the T-cell immunome.

The receptorome, comprising at least 5% of the human genome, encodes receptors that mediate the physiological, pathological and therapeutic responses to a vast number of exogenous and endogenous ligands. Not surprisingly, the majority of approved medications target members of the receptorome. Several in silico and physical screening approaches have been devised to mine the receptorome efficiently for the discovery and validation of molecular targets for therapeutic drug discovery. Receptorome screening has also been used to discover, and thereby avoid, the molecular targets responsible for serious and unforeseen drug side effects.

The macrolide rapamycin is used clinically to treat graft rejection and restenosis. Mammalian target of rapamycin (mTOR) is a central controller of cellular and organism growth that integrates nutrient and hormonal signals, and regulates diverse cellular processes. New studies have linked mTOR to several human diseases including cancer, diabetes, obesity, cardiovascular diseases and neurological disorders. Recent data have also revealed that mTOR is involved in the regulation of lifespan and in age-related diseases. These findings demonstrate the importance of growth control in the pathology of major diseases and overall human health, and underscore the therapeutic potential of the mTOR pathway.

It is generally acknowledged that a crucial event in the initiation and evolution of cancer is the acquisition of a genomic instability phenotype. This review focuses on mechanisms of chromosomal instability including aneuploidy, chromosome rearrangement and breakage-fusion-bridge cycles. The role of micronutrient deficiency, such as folate deficiency, in the causation of chromosomal instability is briefly reviewed and the concept of recommended dietary allowances for genomic stability is introduced. In addition, the techniques for measuring the various chromosomal instability events are discussed with a focus on the cytokinesis-block micronucleus assay as an almost complete system for measuring these various genetic mishaps.

Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders and memory impairments. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose and brain, amplifying local action. Obese humans and rodents show increased 11beta-HSD1 in adipose tissue. Transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome. Conversely, 11beta-HSD1 knockout mice have a 'cardioprotective' phenotype, whose effects are also seen with 11beta-HSD1 inhibitors in rodents. However, any major metabolic effects of 11beta-HSD1 inhibition in humans are, as yet, unreported. 11beta-HSD1 null mice also resist cognitive decline with ageing, and this is seen in humans with a prototypic inhibitor. Thus 11beta-HSD1 inhibition is an emerging pleiotropic therapeutic target.

Microarray analyses reveal global changes in gene expression in response to environmental changes and, thus, are well suited to providing a detailed picture of bacterial responses to antibiotic treatment. These responses are represented by patterns of gene expression, termed expression signatures, which provide insight into the mechanism of action of antibiotics as well as the general physiological responses of bacteria to antibiotic-related stresses. The complexity of such signatures is challenging the notion that antibiotics act on single targets and this is consistent with the concept that there are multiple targets coupled with common stress responses. A more detailed knowledge of how known antibiotics act should reveal new strategies for antimicrobial drug discovery.

During the past decade we witnessed a rapid advance in the new field of chemical science, combinatorial chemistry. The pharmaceutical industries invested heavily in accelerating the development of this new technology. As a result, it has become an extremely important tool in lead identification and optimization in current pharmaceutical research. It also quickly crossed the boundaries of the original chemical discipline and demonstrated great potential in many other important areas, such as searching for novel and highly efficient catalysts and superconductive material. Researchers from both academic and industrial laboratories have directed great effort towards the development of novel strategies for combinatorial synthesis.

Web-based technologies, coupled with a drive for improved communication between scientists, have resulted in the proliferation of scientific opinion, data and knowledge at an ever-increasing rate. The availability of tools to host wikis and blogs has provided the necessary building blocks for scientists with only a rudimentary understanding of computer software science to communicate to the masses. This newfound freedom has the ability to speed up research and sharing of results, develop extensive collaborations, conduct science in public, and in near-real time. The technologies supporting chemistry, while immature, are fast developing to support chemical structures and reactions, analytical data support and integration to related data sources via supporting software technologies. Communication in chemistry is already witnessing a new revolution.

Bioinformatics has, out of necessity, become a key aspect of drug discovery in the genomic revolution, contributing to both target discovery and target validation. The author describes the role that bioinformatics has played and will continue to play in response to the waves of genome-wide data sources that have become available to the industry, including expressed sequence tags, microbial genome sequences, model organism sequences, polymorphisms, gene expression data and proteomics. However, these knowledge sources must be intelligently integrated.

For the past decade the pharmaceutical industry has experienced a steady decline in productivity and a striking observation is that the decline coincided with the introduction of target-based drug discovery. The target-based approach can very effectively develop novel treatments for a validated target, but the process of target validation is complex and associated with a high degree of uncertainty. The purpose of this paper is to analyse these aspects in detail to determine if weaknesses in this part of the drug discovery path might explain why this paradigm has not resulted in increased productivity over the traditional in vivo approach, considering its superiority in screening capacity and its ability to define rational drug discovery programs.