Reviews & Analysis

Marine natural products provide a rich source of drug leads. Using selected examples, Molinski and colleagues review the history of marine natural drug development, examine the unique challenges in this field, and discuss recent advances that may expand the promise of 'drugs from the sea'.

This Opinion highlights some of the recent failures in the clinical trials of chemokine receptor antagonists, explores possible reasons as to why these might have occurred and looks at potential solutions to generate effective chemokine receptor antagonist therapeutics.

Endoplasmic reticulum (ER) stress is induced following the accumulation of unfolded proteins in the ER. This triggers the unfolded protein response, which initially acts to compensate for damage, but if prolonged or excessive can trigger cell death. Here, Reed and colleagues discuss the role of ER-initiated cell death pathways in diseases including neurodegeneration, hypoxia, heart disease, diabetes and immune disorders, while identifying promising therapeutic targets.

Apoptosis can be induced by activating/stabilizing p53, and by inhibiting NF-κB. Now, it has been found that a surprising number of small molecules can do both. This article describes the principles behind such dual activity, discusses current candidate molecules and provides an outlook to their future development as anticancer drugs.

The p53 tumour suppressor pathway is an attractive target for the development of anticancer therapies. This Perspective highlights recent progress with agents that modulate components of the p53 pathway — in particular, p53 itself and its negative regulator MDM2 — focusing on how studies of their genetic variations, including mutations in cancer cells and inherited polymorphisms, could help tailor the use of existing agents and aid the development of novel drugs.

The pro-survival BCL-2 family of proteins provides exciting drug targets for the selective induction of apoptosis in cancer cells, in which these proteins are often overexpressed. Lessene and colleagues review the preclinical and clinical data for BCL-2 antagonists, and recommend criteria for establishing the mode of action for this new drug class.

Pro-apoptotic receptor agonists have a remarkable ability to selectively induce apoptosis in a wide spectrum of malignant cells. Ashkenazi discusses the scientific rationale, emerging clinical data and future potential for this exciting new class of anti-cancer drugs.

Novel immunomodulatory agents have considerably improved the treatment of multiple sclerosis in recent years, but inhibiting disease progression remains a central challenge. This article describes how advances in the understanding of the immunopathogenesis of multiple sclerosis have identified a range of novel targets for intervention and potential therapeutic agents acting at various steps in the pathogenic cascade, including different aspects of T-cell and B-cell function and neuroprotective strategies.

Despite improvements in European regulatory standards and procedures, the occurrence of failed or problematic marketing authorization applications for biotechnological products remains common. Here, Schäffner-Dallmann and Schneider identify common regulatory concerns and consider strategies that may help prevent such issues.

Cardiac glycosides, a diverse family of naturally derived compounds that inhibit Na⁺/K⁺-ATPase, have been used for many years for the treatment of heart failure and atrial arrhythmia. This article discusses recent evidence highlighting additional signal transduction roles for Na⁺/K⁺-ATPase, and associated potential new therapeutic appplications for glycoside-based drugs in a range of diseases — most notably cancer, for which the first generation of such agents are currently in clinical trials.

The wealth of genomic data for pathogens that cause tropical diseases hold considerable promise for the discovery of novel drugs. An international consortium describes how the TDR Targets database integrates this data with related biochemical and pharmacological data to facilitate the identification and prioritization of drug targets.

With no specific cures for most acquired chronic kidney diseases, current efforts are focused on preventing disease progression. Here, Remuzzi and colleagues discuss examples of novel drugs and biologics that might be used to target the inflammatory and profibrotic process, and glomerular injury, highlighting results from recent clinical trials.

The highly conserved family of sirtuin proteins target multiple substrates, affecting a diverse range of cellular functions. Following the emergence of their potential role as regulators of mammalian lifespan, Lavu and colleagues discuss specific sirtuins that may be targeted in the treatment of diseases of ageing, including neurodegenerative and cardiovascular diseases, type 2 diabetes, and cancer.

Histone deacetylases (HDACs) are potentially useful therapeutic targets for a broad range of human disorders. Here, Kazantsev and Thompson discuss how HDAC inhibition could correct transcriptional defects and other acetylation-dependent impairments, and so could be used as treatments for a number of neurodegenerative diseases.

The recent discovery of the ST2 receptor ligand — interleukin-33 — has provided new insight into the importance of ST2 signalling as a mediator of inflammation. Now, an additional role for this pathway as a novel cardioprotective paracrine system is emerging. Here, Kakkar and Lee review these roles and discuss the therapeutic potential of targeting this pathway to treat associated diseases such as asthma, rheumatoid arthritis, atherosclerosis and heart failure.

The association of genetic profiles to drug response is helping to expedite the development of new drugs and diagnostic tests. Roses discusses the considerations that have to be taken into account when identifying pharmacogenetic variants associated with responses to drugs and designing clinically relevant tests.

Drug regulatory agencies face the challenge of striking the appropriate balance between the need for rapid access to new drugs and the need to obtain comprehensive data on their benefit/risk profiles. This article highlights the scientific and regulatory issues involved, discusses regulatory strategies to address these issues, and speculates on future directions, such as a life-cycle approach to drug regulation.

The potential for cost savings from the introduction of 'follow-on' versions of protein therapeutics is a major focus of the ongoing debate around the creation of a regulatory pathway for the abbreviated approval of such products. Lanthier and colleagues explore the economic issues relevant to this debate by assessing total sales, product complexity and patent expiry for current protein products.

In the past decade, the ability of nuclear magnetic resonance (NMR) spectroscopy to provide information on intermolecular interactions that is valuable in drug discovery has been increasingly appreciated. Pellecchia and colleagues provide their collective evaluation of the major applications of NMR in drug discovery, focusing on hit and lead generation, and critically analyse its current and potential utility.

Several nanoscaled systems for cancer therapy are approved or in clinical trials. Here, Davis and colleagues discuss the key properties of nanotherapeutics for cancer, summarize clinical findings with first- and second-generation nanoparticles, and discuss the issues involved in translating experimental nanotherapeutics to the clinic.