Nature Reviews Drug Discovery

Published by Nature Publishing Group
Online ISSN: 1474-1784
Publications
Article
The human genome encodes 40 voltage-gated K(+) channels (K(V)), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca(2+) signalling and cell volume, to driving cellular proliferation and migration. K(V) channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting K(V) channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the K(V)1 subfamily, the K(V)7 subfamily (also known as KCNQ), K(V)10.1 (also known as EAG1 and KCNH1) and K(V)11.1 (also known as HERG and KCNH2) channels.
 
Article
Evolving studies with several different targeted therapeutic agents are demonstrating that patients with genomic alterations of the target, including amplification, translocation and mutation, are more likely to respond to the therapy. Recent studies indicate that numerous components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway are targeted by amplification, mutation and translocation more frequently than any other pathway in cancer patients, with resultant activation of the pathway. This warrants exploiting the PI3K/AKT pathway for cancer drug discovery.
 
Article
Aberrant activation of the Wnt pathway is implicated in driving the formation of various human cancers, particularly those of the digestive tract. Inhibition of aberrant Wnt pathway activity in cancer cell lines efficiently blocks their growth, highlighting the great potential of therapeutics designed to achieve this in cancer patients. Here we provide an overview of the promise and pitfalls of current drug development strategies striving to inhibit the Wnt pathway and present new opportunities for therapeutic intervention.
 
Article
The recent outbreaks of avian influenza A (H5N1) virus, its expanding geographic distribution and its ability to transfer to humans and cause severe infection have raised serious concerns about the measures available to control an avian or human pandemic of influenza A. In anticipation of such a pandemic, several preventive and therapeutic strategies have been proposed, including the stockpiling of antiviral drugs, in particular the neuraminidase inhibitors oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GlaxoSmithKline). This article reviews agents that have been shown to have activity against influenza A viruses and discusses their therapeutic potential, and also describes emerging strategies for targeting these viruses.
 
| Approved and marketed drug-cyclodextrin* complexes in various world markets
| Examples of cyclodextrin pendent polymers
| Examples of cyclodextrin-containing polymers used for the delivery of nucleic acids
Article
Cyclodextrins are cyclic oligomers of glucose that can form water-soluble inclusion complexes with small molecules and portions of large compounds. These biocompatible, cyclic oligosaccharides do not elicit immune responses and have low toxicities in animals and humans. Cyclodextrins are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current cyclodextrin-based therapeutics are described and possible future applications discussed. Cyclodextrin-containing polymers are reviewed and their use in drug delivery presented. Of specific interest is the use of cyclodextrin-containing polymers to provide unique capabilities for the delivery of nucleic acids.
 
Article
Modulating protein-protein interactions involved in disease pathways is an attractive strategy for developing drugs, but remains a challenge to achieve. One approach is to target certain domains within proteins that mediate these interactions. One example of such a domain is the PDZ domain, which is involved in interactions between many different proteins in a variety of cellular contexts. Because PDZ domains have well-defined binding sites, they are promising targets for drug discovery. However, there is still much to learn about the function of these domains before drugs targeting PDZ interactions can become a reality.
 
Article
Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.
 
Article
The first cancer-targeted microRNA (miRNA) drug - MRX34, a liposome-based miR-34 mimic - entered Phase I clinical trials in patients with advanced hepatocellular carcinoma in April 2013, and miRNA therapeutics are attracting special attention from both academia and biotechnology companies. Although miRNAs are the most studied non-coding RNAs (ncRNAs) to date, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognized. Here, we summarize the roles of miRNAs and lncRNAs in cancer, with a focus on the recently identified novel mechanisms of action, and discuss the current strategies in designing ncRNA-targeting therapeutics, as well as the associated challenges.
 
Article
Current anti-obesity drugs aim to reduce food intake by either curbing appetite or suppressing the craving for food. However, many of these agents have been associated with severe psychiatric and/or cardiovascular side effects, highlighting the need for alternative therapeutic strategies. Emerging knowledge on the role of the hypothalamus in enabling the central nervous system to adapt to the changing environment - by managing peripheral tissue output and by regulating higher brain functions - may facilitate the discovery of new agents that are more effective and have an acceptable benefit-risk profile. Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.
 
Article
Although our knowledge of the pathophysiology of schizophrenia has increased, treatments for this devastating illness remain inadequate. Here, we critically assess rodent models and behavioural end points used in schizophrenia drug discovery and discuss why these have not led to improved treatments. We provide a perspective on how new models, based on recent advances in the understanding of the genetics and neural circuitry underlying schizophrenia, can bridge the translational gap and lead to the development of more effective drugs. We conclude that previous serendipitous approaches should be replaced with rational strategies for drug discovery in integrated preclinical and clinical programmes. Validation of drug targets in disease-based models that are integrated with translationally relevant end point assessments will reduce the current attrition rate in schizophrenia drug discovery and ultimately lead to therapies that tackle the disease process.
 
Article
According to a public announcement by the US National Institutes of Health, “Biofilms are medically important, accounting for over 80% of microbial infections in the body”. Yet bacterial biofilms remain poorly understood and strategies for their control remain underdeveloped. Standard antimicrobial treatments typically fail to eradicate biofilms, which can result in chronic infection and the need for surgical removal of afflicted areas. The need to create effective therapies to counter biofilm infections presents one of the most pressing challenges in anti-bacterial drug development. In this article, the mechanisms that underlie biofilm resistance to antimicrobial chemotherapy will be examined, with particular attention being given to potential avenues for the effective treatment of biofilms.
 
Article
The past twenty five years have seen an explosion in the creation and discovery of new medicinal agents. Related innovations in drug delivery systems have not only enabled the successful implementation of many of these novel pharmaceuticals, but have also permitted the development of new medical treatments with existing drugs. The creation of transdermal delivery systems has been one of the most important of these innovations, offering a number of advantages over the oral route. In this article, we discuss the already significant impact this field has made on the administration of various pharmaceuticals; explore limitations of the current technology; and discuss methods under exploration for overcoming these limitations and the challenges ahead.
 
Article
Antibiotic resistance is one of the greatest challenges of the twenty-first century. However, the increasing understanding of bacterial pathogenesis and intercellular communication has revealed many potential strategies to develop novel drugs to treat bacteria-mediated disease. Interference with bacterial virulence and/or cell-to-cell signalling pathways is an especially compelling approach, as it is thought to apply less selective pressure for the development of bacterial resistance than traditional strategies, which are aimed at killing bacteria or preventing their growth. Here, we discuss the mechanisms of bacterial virulence and present promising anti-virulence strategies and compounds for the future treatment of bacterial infections.
 
Article
The significant involvement of the gut microbiota in human health and disease suggests that manipulation of commensal microbial composition through combinations of antibiotics, probiotics and prebiotics could be a novel therapeutic approach. A systems perspective is needed to help understand the complex host-bacteria interactions and their association with pathophysiological phenotypes so that alterations in the composition of the gut microbiota in disease states can be reversed. In this article, we describe the therapeutic rationale and potential for targeting the gut microbiota, and discuss strategies and systems-oriented technologies for achieving this goal.
 
Article
In the 10 years that have passed since the Nobel prize-winning discovery of RNA interference (RNAi), billions of dollars have been invested in the therapeutic application of gene silencing in humans. Today, there are promising data from ongoing clinical trials for the treatment of age-related macular degeneration and respiratory syncytial virus. Despite these early successes, however, the widespread use of RNAi therapeutics for disease prevention and treatment requires the development of clinically suitable, safe and effective drug delivery vehicles. Here, we provide an update on the progress of RNAi therapeutics and highlight novel synthetic materials for the encapsulation and intracellular delivery of nucleic acids.
 
Article
Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal diffuse fibrosing lung disease, with a mortality rate that exceeds that of many cancers. Recently, there have been many clinical trials of novel therapies for IPF. The results have mostly been disappointing, although two treatment approaches have shown some efficacy. This Review describes the difficulties of treating IPF and the approaches that have been tried or are in development, and concludes with suggestions of future therapeutic targets and strategies.
 
Article
The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metabolism. New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.
 
Four-cell model of the brain microvasculature.The capillary endothelium shares a basement membrane with pericytes, and >99% of the brain surface of the capillary basement membrane is surrounded by astrocyte foot processes. There is occasional neuronal innervation of the capillary. The permeability properties of the blood–brain barrier are controlled by the endothelial cells, which express high-resistance tight junctions4.
Imaging gene expression in the brain in vivo.C6 rat glioma cells were permanently transfected with a gene that encodes luciferase, and these cells were implanted in the caudate-putamen nucleus of adult rats36. The experimental brain tumours selectively expressed the luciferase gene in vivo, based on measurements of tumour luciferase enzyme activity. a,b | Anti-luciferase peptide nucleic acid (PNA) conjugated to a brain drug-targeting system. c,d | Unconjugated anti-luciferase PNA. Figures a and c are autopsy stains, which show that large experimental tumours are formed. These tumour-bearing rats were given an anti-luciferase peptide nucleic acid (PNA) radiopharmaceutical intravenously two hours before sacrifice and film autoradiography of brain sections. When unconjugated anti-luciferase PNA was administered, there was no specific imaging of the brain tumour in vivo (d). However, when the PNA antisense radiopharmaceutical was conjugated to the brain drug-targeting system, the brain tumour that expressed the luciferase gene was imaged (b). By contrast, when a PNA that was specific to a viral messenger RNA was conjugated to the anti-Tfr MAb and injected intravenously into the tumour-bearing rats, there was no imaging of the experimental brain tumour in vivo36, owing to the absence of the viral mRNA in the brain. MAb, monoclonal antibody; Tfr, rat transferrin receptor. (Reprinted with permission from Ref. 36 © (2000) National Academy of Sciences, USA.)
Non-viral, non-invasive gene targeting to the brain.a | Targeting an exogenous gene encapsulated in a PEGylated immunoliposome (PIL) with a monoclonal antibody to the mouse transferrin receptor (Tfr) results in widespread gene expression in the brain following intravenous administration. The figure shows -galactosidase histochemistry of a section of mouse brain that was removed 48 hours after a single intravenous injection of a -galactosidase expression plasmid51. If the exogenous gene is under the influence of a widely expressed gene promoter, such as the SV40 promoter, the gene is also expressed in TFR-rich organs, such as the liver or spleen47. Conversely, if the expression of the exogenous gene is regulated by a brain-specific promoter, then gene expression is confined to the brain51. This was shown by replacing the SV40 promoter with the 5'-flanking sequence of the gene for the human glial fibrillary acidic protein (GFAP). A -galactosidase expression plasmid, under the influence of the GFAP promoter, was packaged into the interior of a targeted PIL and injected intravenously into mice. Although the -galactosidase gene was widely expressed in the brain, there was no gene expression in peripheral tissues51. These studies show that tissue-specific expression of exogenous genes can be achieved with tissue-specific gene promoters. b | There is no detectable expression of the -galactosidase gene in mouse brain two days after an intravenous injection if the plasmid DNA is packaged into the interior of PILs that were targeted with a non-specific rat immunoglobulin-G control antibody51. (Reprinted with permission from Ref. 51 © (2001) National Academy of Sciences, USA.)
Article
Getting drugs and genes into the brain is a tall order. This is because the presence of the blood-brain barrier prevents many molecules from crossing into the brain. Overcoming this problem will have a profound effect on the treatment of many neurological disorders, allowing larger water-soluble molecules to pass into the brain. Transport vectors, such as endogenous peptides, modified proteins or peptidomimetic monoclonal antibodies, are one way of tricking the brain into allowing these molecules to pass. This article will review such molecular Trojan Horses, and the progress that has been made in the delivery of drugs and genes to the brain.
 
Article
Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu(1) and mGlu(5)), group II (mGlu(2) and mGlu(3)), and group III (mGlu(4), mGlu(7) and mGlu(8)) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu(2/3)) receptors and antagonists for group I (in particular mGlu(5)) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.
 
Article
In February 2010, a quadrivalent conjugate vaccine (Menveo; Novartis Vaccines and Diagnostics) was approved by the US FDA to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 in people aged 11-55 years.
 
Article
Liposomes - microscopic phospholipid bubbles with a bilayered membrane structure - have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs - from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.
 
Article
Treatment of cancer is a double-edged sword: it should be as aggressive as possible to completely destroy the tumour, but it is precisely this aggressiveness which often causes severe side effects - a reason why some promising therapeutics can not be applied systemically. In addition, therapeutics such as cytokines that physiologically function in a para- or autocrine fashion require a locally enhanced level to exert their effect appropriately. An elegant way to accumulate therapeutic agents at the tumour site is their conjugation/fusion to tumour-specific antibodies. Here, we discuss recent preclinical and clinical data for antibody-drug conjugates and fusion proteins with a special focus on drug components that exert their antitumour effects through normal biological processes.
 
Article
Although contemporary treatments cure more than 80% of children with acute lymphoblastic leukaemia (ALL), some patients require intensive treatment and many patients still develop serious acute and late complications owing to the side effects of the treatments. Furthermore, the survival rate for adults with ALL remains below 40%. Therefore, new treatment strategies are needed to improve not only the cure rate but also the quality of life of these patients. Here, we discuss emerging new treatments that might improve the clinical outcome of patients with ALL. These include new formulations of existing chemotherapeutic agents, new antimetabolites and nucleoside analogues, monoclonal antibodies against leukaemia-associated antigens, and molecular therapies that target genetic abnormalities of the leukaemic cells and their affected signalling pathways.
 
Article
The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism. However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states. This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration.
 
Article
The key role of interleukin-17 (IL-17) and T helper 17 (T(H)17) cells in tissue inflammation, autoimmunity and host defence led to the experimental targeting of these molecules in mouse models of diseases as well as in clinical settings. Moreover, the demonstration that IL-17 and T(H)17 cells contribute to local and systemic aspects of disease pathogenesis, as well as the finding that the IL-17-T(H)17 cell pathway is regulated by IL-23, prompted the identification of inhibitors. These inhibitors include biotechnology products that target IL-23 as well as the leading member of the IL-17 family, IL-17A, and one of its receptors, IL-17 receptor A. Several clinical trials of these inhibitors are underway, and positive results have been obtained in psoriasis, rheumatoid arthritis and ankylosing spondylitis. This Review focuses on the current knowledge of the IL-17-T(H)17 cell pathway to better understand the positive as well as potential negative consequences of targeting them.
 
Article
In addition to being a major neurotransmitter in the central nervous system, dopamine can contribute to the modulation of immunity via dopamine receptors expressed on immune cells. A recently published paper in the Journal of Immunology has shown that dopamine causes inflammation in rheumatoid arthritis by inducing the release of interleukin-17 (IL-17) from dendritic cells of the immune system.
 
Article
A Phase III trial for a first-in-class psoriasis drug provides encouraging data, but the emerging agents still have to prove their worth in a crowded autoimmune market.
 
Article
The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders.
 
Article
Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this phosphatase.
 
Article
The growth of research capabilities in emerging economies such as India and China has led many to question the status of innovation in the current leading economies such as the United States. Indeed, lower costs in emerging economies have already led to a substantial increase in the outsourcing of some of the more routine activities involved in pharmaceutical research and development (R&D), such as compound synthesis and preclinical toxicity tests, to organizations in these countries.
 
Article
At around this time every year, companies and regulatory authorities bombard us with so much end-of-year information that it is sometimes hard to keep track of what drug was approved and where. So, in the first in a series of annual reports, we aim to provide you with a concise and informative reference guide to the novel drugs that have been approved by the FDA in the United States and by EMEA (European Agency for the Evaluation of Medicinal Products) in Europe over the previous year, and show how these numbers of approved drugs compare to the tally in recent years.
 
Article
Although the number of new molecular entities approved in 2003 was only marginally higher than in 2002, approvals for innovative drugs were encouraging.
 
Article
A major contributor to the poor performance of the biotechnology and pharmaceutical sectors in 2002 was the US FDA, which held products to an absolute and unnecessarily high standard. As a result, few novel therapeutics were approved and those that were took longer to get through the FDA review process.
 
Article
2003 might have been one of the worst years for unemployment in the pharmaceutical industry, but there are signs that the market could be beginning to improve.
 
Article
The rise in approval numbers is good news, but the list illustrates companies' future growth models.
 
Article
Companies move towards niche products to boost productivity.
 
Article
Much of drug discovery today is predicated on the concept of selective targeting of particular bioactive macromolecules by low-molecular-mass drugs. The binding of drugs to their macromolecular targets is therefore seen as paramount for pharmacological activity. In vitro assessment of drug-target interactions is classically quantified in terms of binding parameters such as IC(50) or K(d). This article presents an alternative perspective on drug optimization in terms of drug-target binary complex residence time, as quantified by the dissociative half-life of the drug-target binary complex. We describe the potential advantages of long residence time in terms of duration of pharmacological effect and target selectivity.
 
Article
What have been some of the past year's key events and trends for the biopharma industry?
 
Article
The US FDA approved 17 new molecular entities (NMEs) and 2 biologic license applications (BLAs) in 2007 (Table 1; Fig. 1), the lowest number recorded since 1983.
 
Article
The Centre for Medicines Research International has noted that the average for the combined success rate at Phase III and submission has fallen to ~50% in recent years. To learn more about the causes for Phase III and submission failures, Thomson Reuters Life Science Consulting analysed the reasons for these failures between 2007 and 2010.
 
Article
Using processed consensus investment research, AVOS Life Sciences has analysed the performance of the top 14 pharmaceutical companies as a group for the period 2008–2013E (Supplementary information S1 (box)). The analysis focuses on the major Rx drug portfolio (MRDP; the collection of branded drugs, each of which is predicted to achieve at least US$500 million in annual sales) of each company as a measure of its overall performance.
 
Article
Specialty products continued to dominate new drug and biologic approvals in the US in a year in which the evolving regulatory environment also featured heavily.
 
Top-cited authors
Claudiu T Supuran
  • University of Florence
Lorenzo Galluzzi
  • Weill Cornell Medical College
Bernard H Munos
  • Milken Institute
Dunyaporn Trachootham
  • Mahidol University
Peng Huang
  • Sun Yat-Sen University Cancer Center