Reviews & Analysis

The threat of an influenza pandemic has heightened the need for therapeutic strategies to combat this virus. This article provides a historical perspective on the discovery and development of two drugs that are at the forefront of our defences against influenza — the sialdiase inhibitors zanamivir and oseltamivir — highlighting the value of structure-based drug design in this process.

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.

HIV has been the most active field of antiviral drug research and development since the discovery of the virus a quarter of a century ago. Flexner provides an overview of current opportunities and novel targets in HIV drug discovery, and analyses the central questions pertinent for the next 25 years of drug development for HIV.

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.

To fully realize the potential of molecularly targeted therapies for cancer and other human diseases, a new level of knowledge about the complex cellular control circuitry is required. Here, the authors explore mathematical paradigms that facilitate the design of network-targeted anticancer drugs.

The digital information revolution has led to the rapid development of many countries, causing the pharmaceutical industry to face a new array of Asia-specific challenges. Epstein discusses how understanding Asia's diverse cultures, talents and markets will bring about success for the industry.

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.

Despite increased pharmaceutical investment, few novel molecular entities that address new pain mechanisms have entered the clinic. Dionne and colleagues discuss factors contributing to this lack of innovation and highlight strategies to translate new knowledge into more efficacious and safer treatments.

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.

Alliances are now a key component of the research and development strategies of most major pharmaceutical companies. Jones summarizes recent trends in alliance formation and discuss approaches to minimize risk in alliances, which are growing in importance as alliance activity increases.

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.