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Interferons (IFNs) provide fundamental cellular defence mechanisms against viral infections and cancer. On the 50th anniversary of the discovery of IFNs, the authors provide a comprehensive overview of IFN biology, human therapeutic applications and potential drug targets within the IFN system.
Drug development for HIV has been the major driving force in antiviral research. The strategies that are now being pursued for combating hepatitis C virus (HCV) are remarkably reminiscent of those established for HIV. Here, De Clercq reviews aspects of the medicinal chemistry and history of drug design for HIV and HCV.
Insights into the life cycle of hepatitis C virus (HCV) have facilitated the development of a number of innovative agents. Here, Manns and colleagues discuss the obstacles in current HCV management, the key challenges for new HCV antivirals and potential future therapeutic options.
Genetic factors may underlie susceptibility to serious adverse drug reactions (SADRs). Here, the authors discuss three SADRs — liver injury, myotoxicity and long QT syndrome — and consider the challenges that need to be overcome to identify predisposing genotypes, which might improve patient management.
Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and discusses the likely options and paths for the therapeutic exploitation of H2S.
Target-based drug discovery has not been as successful as was hoped, in part owing to the complexities of biological systems and disease pathophysiology. This Review explores experimental strategies for the retrospective identification of molecular targets that underlie phenotypic drug effects (target deconvolution) — strategies that might be used to aid efficient drug development.
Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. This article discusses recent advances in the understanding of the biological role of RARs and RXRs and their implications for the design of selective receptor modulators for cancer and metabolic diseases.
Chronic myeloid leukaemia caused by the mutant BCR–ABL kinase has been successfully treated with inhibitors of this kinase, such as imatinib, but mutations within the kinase can result in resistance to these drugs. Quintás-Cardama and colleagues discuss novel BCR–ABL inhibitors that have the potential to overcome such resistance.
In this Review, Clemmons discusses how strategies to utilize IGF1's growth stimulating and anabolic properties are being pursued to treat short stature, catabolism and diabetes, and highlights the potential benefit of IGF1 antagonism in cancer therapy.
Retinoic acid receptors (RARs) are important drug targets for cancer therapy and prevention, and the potential of rexinoids for the treatment of metabolic diseases is increasingly being recognized. This article reviews recent structural data for RARs and retinoid X receptors (RXRs), discusses strategies in the design of selective RXR and RAR modulators, and consider lessons that can be learned for the design of selective nuclear-receptor modulators in general.
Altered muscarinic acetylcholine receptor (mAChR) activity is implicated in many disorders including Alzheimer's disease, schizophrenia, pain, obesity and diabetes, but lack of knowledge of the precise functional roles of the individual mAChR subtypes has hampered drug development. Wess and colleagues review recent insights gained frommAChR-knockout mice that are helping to address this issue and discuss the therapeutic potential of subtype-selective mAChR modulation.
Sunitinib is a multitargeted kinase inhibitor that has recently been approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumours. Raymond and colleagues summarize the discovery and development of sunitinib, and discuss key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance.
In their Review, the authors describe animal and human laboratory paradigms used to investigate the pathophysiology of nicotine dependence, and propose how their predictive clinical validity might be improved, thereby enhancing the development of new medications for smoking cessation.
In vitromodels of the blood–brain barrier (BBB) allow predictions of brain uptake for candidate drugs. Providing guidance through the plethora of BBB models, the authors discuss the pros and cons of different models, and their applications at various stages of drug discovery and development.
Hypertrophy of heart cells stimulated by pathological stress from cardiovascular disease increases the risk of morbidity and mortality, and inhibition of such hypertrophy is attracting increasing attention as a therapeutic strategy. McKinsey and Kass provide a comprehensive summary of small-molecule inhibitors of cardiac hypertrophy and intracellular signalling pathways that offer further promising therapeutic targets.
Toxicity is a leading cause of attrition at all stages of the drug development process. In their Review, Kramer and colleagues discuss how the early application of preclinical safety assessment can aid the design of safer pharmaceutical lead candidates.
Peroxynitrite — the product of the reaction of nitric oxide with superoxide radical — is a potent inducer of cell death. Szabó and colleagues review the biochemistry and pathophysiology of peroxynitrite and discuss pharmacological strategies to attenuate its toxic effects, which have lead to potential drug development candidates for cardiovascular, inflammatory and neurodegenerative diseases.
Protein-fragment complementation assays (PCAs) can be used to explore the dynamics of protein–protein interactions, and regulatory responses to intrinsic or extrinsic perturbations of biochemical pathways. Michnick and colleagues discuss the rationale behind the PCA design, and its manifold applications for drug discovery.
Members of the RAS superfamily of monomeric GTPases are promising anticancer targets, but previous attempts to therapeutically modulate their activity, which have focused on the development of farnesyltransferase inhibitors, have not proved as successful as hoped. The authors discuss novel approaches targeting prenylation and post-prenylation modifications and the functional regulation of GDP/GTP exchange as exciting alternatives for anticancer therapy.
With the development of genome-wide RNAi approaches, the cost and time involved in target identification, validation and other aspects of drug discovery could be significantly reduced. Ashworth and colleagues review technologies available for RNAi screens and discuss how cancer drug discovery can benefit from their application.