Review Articles in 2008

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'.

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 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.

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.

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.

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.

Tetraspanins are a family of transmembrane proteins with emerging roles in both normal and pathological processes including development, fertilization, malignancy, immune-cell function and infectious disease. Here, Hemler reviews the functions of specific tetraspanins with the potential to be therapeutically targeted, and proposes possible strategies that may be pursued.

Here, Haskó and colleagues discuss how an increased awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.

In this Review, Lambert describes the physiology and potential clinical applications of nociceptin/orphanin FQ and its receptor. This peptide–receptor system has been implicated in a wide range of biological functions such as pain, drug abuse, cardiovascular control and immunity.

The recent awareness that bile acids act as complex metabolic integrators and signalling factors has led to the recognition of bile-acid signalling as a potential novel therapeutic target in metabolic disease. Thomas and colleagues overview the metabolic roles of bile acids and discuss approaches to modulate their signalling pathways in the treatment of disorders including obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis.

Pseudoreceptor models can provide a valuable tool for drug design in cases where a high-resolution structure of the target is not available. This article reviews pseudoreceptor modelling techniques, presenting recent applications in hit and lead finding, and critically discusses the prerequisites, advantages and limitations of the various approaches.

Natural products comprised of a macrocycle ring structure have proven their therapeutic applications as antibiotics, immunosuppressants as well as anticancer agents. Despite this, macrocyclic compounds remain under-explored. Terrett and colleagues review the properties and features of current macrocycle drugs, emphasizing the vast potential of synthetic macrocyles in drug discovery.

There is increasing interest in the role of purinergic signalling in CNS disorders, but few modulators have reached the clinic. Here, Burnstock provides an overview of the role of purinergic signalling in specific disorders, including brain trauma, ischaemia, neurodegenerative, neuroinflammatory and neuropsychiatric diseases, and highlights specific purinergic receptor subtypes that represent promising therapeutic targets.

Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility.