Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer.

Malaria kills approximately 1–2 million people every year, mostly in sub-Saharan Africa and in Asia. These deaths are at the most severe end of a scale of pathologies affecting approximately 500 million people per year. Much of the pathogenesis of malaria is caused by inappropriate or excessive immune responses mounted by the body to eliminate malaria parasites. In this review, we examine the evidence that immunopathology is responsible for malaria disease in the context of what we have learnt from animal models of malaria. In particular, we look in detail at the processes involved in endothelial cell damage leading to syndromes such as cerebral malaria, as well as generalised systemic manifestations such as anaemia, cachexia and problems with thermoregulation of the body. We also consider malaria in light of the variation of the severity of disease observed among people, and discuss the contribution from animal models to our understanding of this variation. Finally, we discuss some of the implications of immunopathology, and of host and parasite genetic variation, for the design and implementation of anti-malarial vaccines.

Wilms tumour (WT) is the most common paediatric kidney cancer and affects approximately one in 10 000 children. The tumour is associated with undifferentiated embryonic lesions called nephrogenic rests (NRs) or, when diffuse, nephroblastomatosis. WT or NRs can occur in both kidneys, termed bilateral disease, found in only 5–8% of cases. Management of bilateral WT presents a major clinical challenge in terms of maximising survival, preserving renal function and understanding underlying genetic risk. In this review, we compile clinical data from 545 published cases of bilateral WT and discuss recent progress in understanding the molecular basis of bilateral WT and its associated precursor NRs in the context of the latest radiological, surgical and epidemiological features.

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis.

Retinoids (derivatives of vitamin A) are signalling molecules that play important roles in cell growth, differentiation and death. Retinoids act through two types of receptors – retinoic acid receptors (RARα, RARβ and RARγ) and retinoid X receptors (RXRα, RXRβ and RXRγ) – which themselves act as ligand-dependent transcription factors. Retinoids are of special interest in cancer research owing to their antiproliferative and cancer-preventative properties. They have been used successfully to cure acute promyelocytic leukaemia (APL) and can suppress carcinogenesis in a variety of tissue types (e.g. skin, lung, breast and oral cancers). Extensive research efforts have been dedicated to elucidating the molecular and cellular networks that are induced by retinoids, and this has recently yielded novel insights into how retinoids can both prevent and combat cancer.

Proteins that are exported from the cell, or targeted to the cell surface or other organelles, are synthesised and assembled in the endoplasmic reticulum and then delivered to their destinations. Point mutations – the most common cause of human genetic diseases – can inhibit folding and assembly of the protein in the endoplasmic reticulum. The unstable or partially folded mutant protein does not undergo trafficking and is usually rapidly degraded. A potential therapy for protein misfolding is to correct defective protein folding and trafficking using pharmacological chaperones. Pharmacological chaperones are substrates or modulators that appear to function by directly binding to the partially folded biosynthetic intermediate to stabilise the protein and allow it to complete the folding process to yield a functional protein. Initial clinical studies with pharmacological chaperones have successfully reduced clinical symptoms of disease. Therefore, pharmacological chaperones show great promise as a new class of therapeutic agents that can be specifically tailored for a particular genetic disease.

Muscular dystrophies are a group of diseases characterised by the primary wasting of skeletal muscle, which compromises patient mobility and in the most severe cases originate a complete paralysis and premature death. Existing evidence implicates calcium dysregulation as an underlying crucial event in the pathophysiology of several muscular dystrophies, such as dystrophinopathies, calpainopathies or myotonic dystrophy among others. Duchenne muscular dystrophy is the most frequent myopathy in childhood, and calpainopathy or LGMD2A is the most common form of limb-girdle muscular dystrophy, whereas myotonic dystrophy is the most frequent inherited muscle disease worldwide. In this review, we summarise recent advances in our understanding of calcium ion cycling through the sarcolemma, the sarcoplasmic reticulum and mitochondria, and its involvement in the pathogenesis of these dystrophies. We also discuss some of the clinical implications of recent findings regarding Ca2+ handling as well as novel approaches to treat muscular dystrophies targeting Ca2+ regulatory proteins.

Intrahepatic cholestasis of pregnancy (ICP) occurs mainly in the third trimester and is characterised by pruritus and elevated serum bile acid levels. ICP is associated with an increased perinatal risk and higher rates of foetal morbidity and mortality. Although the pathogenesis of this disease is unknown, a genetic hypersensitivity to female hormones (oestrogen and/or progesterone) or their metabolites is thought to impair bile secretory function. Recent data suggest that mutations or polymorphisms of genes expressing hepatobiliary transport proteins or their nuclear regulators may contribute to the development and/or severity of ICP. Unidentified environmental factors may also influence pathogenesis of the disease. This review summarises current knowledge on the potential mechanisms involved in ICP at the molecular level.

Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is an integral part of physiological processes such as embryonic development, the female reproductive cycle and wound healing. Angiogenesis is also central to a variety of pathologies including cancer, where it is recognised as being crucial for the growth of solid tumours. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, most notably MMP-2 and -9 and membrane-type-1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, liberation of angiogenic factors, production of endogenous angiogenic inhibitors, and the unmasking of cryptic biologically relevant sites in ECM components. This review brings together what is currently known about the functions of the MMPs and the closely related adamalysin metalloproteinase (ADAM) family in angiogenesis, and discusses how this information might be useful in manipulation of the angiogenic process, with a view to controlling aberrant neovascularisation.

Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth condition with an increased risk of developing embryonic tumours, such as Wilms' tumour. The cardinal features are abdominal wall defects, macroglossia and gigantism. BWS is generally sporadic; only 10–15% of cases are familial. A variety of molecular aberrations have been associated with BWS. The only mutations within a gene are loss-of-function mutations in the CDKN1C gene, which codes for an imprinted cell-cycle regulator. CDKN1C mutations appear to be particularly associated with umbilical abnormalities, but not with increased predisposition to Wilms' tumour. In the remaining BWS subgroups, a disturbance of the tight epigenetic regulation of gene expression (patUPD 11p, microdeletions or epimutations) seems to be the cause of the syndrome. Here we describe the clinical presentation of BWS and its dissociation from phenotypically overlapping overgrowth syndromes. We then review the current concepts of causative molecular genetic and epigenetic mechanisms, and discuss future directions of research.

Macroautophagy and chaperone-mediated autophagy (CMA) are the two main mammalian lysosomal proteolytic systems. In macroautophagy, double-membrane structures engulf organelles and other intracellular constituents through a highly regulated process that involves the formation of autophagic vacuoles and their fusion with lysosomes. In CMA, selected proteins are targeted through a nonvesicular pathway to a transport complex at the lysosomal membrane, through which they are threaded into the lysosomes and degraded. Autophagy is important in development, differentiation, cellular remodelling and survival during nutrient starvation. Increasing evidence suggests that autophagic dysregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as Parkinson disease (PD). Evidence from post-mortem material, transgenic mice, and animal and cellular models of PD suggests that both major autophagic pathways are malfunctioning. Numerous connections exist between proteins genetically linked to autosomal dominant PD, in particular α-synuclein and LRRK2, and autophagic pathways. However, proteins involved in recessive PD, such as PINK1 and Parkin (PINK2), function in the process of mitophagy, whereby damaged mitochondria are selectively engulfed by macroautophagy. This wealth of new data suggests that both autophagic pathways are potential targets for therapeutic intervention in PD and other related neurodegenerative conditions.

Inhibiting apoptosis is widely accepted as a necessary step in the transition from normal to cancer cells, and most cancer therapies exert their effects by indirectly reversing this process. Commitment to apoptosis is caused by permeabilisation of the outer mitochondrial membrane – a process regulated by the binding between different members of the Bcl-2 family. Furthermore, Bcl-2 family members also bind to the endoplasmic reticulum, where they modify processes such as the unfolded-protein response and autophagy that also cause or modify different types of cell death. With the growing understanding of the importance of the Bcl-2 family as crucial regulators of the decision to initiate apoptosis, much effort has been directed at developing small molecules that modify function by directly binding to Bcl-2 proteins. Preclinical experiments have confirmed that these agents kill cancer cells and overcome chemotherapy resistance. Two of these drugs are in the initial stages of clinical development (ABT-263 and obatoclax), and early results show clinical efficacy at tolerable doses. Important questions for the future include the role of these drugs as monotherapy versus combination therapy with other anticancer drugs, and the related issue of the relative toxicity to cancerous versus normal cells.

Pelizaeus–Merzbacher disease (PMD) is a recessive X-linked dysmyelinating disorder of the central nervous system (CNS). The most frequent cause of PMD is a genomic duplication of chromosome Xq22 including the region encoding the dosage-sensitive proteolipid protein 1 (PLP1) gene. The PLP1 duplications are heterogeneous in size, unlike duplications causing many other genomic disorders, and arise by a distinct molecular mechanism. Other causes of PMD include PLP1 deletions, triplications and point mutations. Mutations in the PLP1 gene can also give rise to spastic paraplegia type 2 (SPG2), an allelic form of the disease. Thus, there is a spectrum of CNS disorder from mild SPG2 to severe connatal PMD. PLP1 encodes a major protein in CNS myelin and is abundantly expressed in oligodendrocytes, the myelinating cells of the CNS. Significant advances in our understanding of PMD have been achieved by investigating mutant PLP1 in PMD patients, animal models and in vitro studies. How the different PLP1 mutations and dosage effects give rise to PMD is being revealed. Interestingly, the underlying causes of pathogenesis are distinct for each of the different genetic abnormalities. This article reviews the genetics of PMD and summarises the current knowledge of causative molecular and cellular mechanisms.

The small and large intestine contain the largest number of macrophages in the body and these cells are strategically located directly underneath the epithelial layer, enabling them to sample the lumen. Such intestinal macrophages have a different phenotype from other tissue macrophages in that they ingest and may kill microbes but they do not mediate strong pro-inflammatory responses upon microbial recognition. These properties are essential for maintaining a healthy intestine. It is generally accepted that tolerance to the intestinal flora is lost in inflammatory bowel diseases, and genes involved in microbial recognition, killing and macrophage activation have already been associated with these diseases. In this review, we shed light on the intestinal macrophage and how it influences intestinal immunity.

The prevalence of obesity and diabetes, which are heritable traits that arise from the interactions of multiple genes and lifestyle factors, continues to rise worldwide, causing serious health problems and imposing a substantial economic burden on societies. For the past 15 years, candidate gene and genome-wide linkage studies have been the main genetic epidemiological approaches to identify genetic loci for obesity and diabetes, yet progress has been slow and success limited. The genome-wide association approach, which has become available in recent years, has dramatically changed the pace of gene discoveries. Genome-wide association is a hypothesis-generating approach that aims to identify new loci associated with the disease or trait of interest. So far, three waves of large-scale genome-wide association studies have identified 19 loci for common obesity and 18 for common type 2 diabetes. Although the combined contribution of these loci to the variation in obesity and diabetes risk is small and their predictive value is typically low, these recently identified loci are set to substantially improve our insights into the pathophysiology of obesity and diabetes. This will require integration of genetic epidemiological methods with functional genomics and proteomics. However, the use of these novel insights for genetic screening and personalised treatment lies some way off in the future.

Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital malformation and intellectual disability syndrome, with clinical characteristics that encompass a wide spectrum and great variability. Elucidation of the biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol deficiency syndrome caused by mutation in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models, especially models of brain cells, would be useful, and in vivo human studies are also essential. Biomarker development will be crucial in facilitating clinical trials in this rare condition, because the clinical phenotype can change over many years. Additional research in these and other areas is critical if we are to make headway towards ameliorating the effects of this devastating condition.

The complex neurodegeneration underlying Alzheimer disease (AD), although incompletely understood, is characterised by an aberrant re-entry into the cell cycle in neurons. Pathological evidence, in the form of cell cycle markers and regulatory proteins, suggests that cell cycle re-entry is an early event in AD, which precedes the formation of amyloid-β plaques and neurofibrillary tangles (NFTs). Although the exact mechanisms that induce and mediate these cell cycle events in AD are not clear, significant advances have been made in further understanding the pathological role of cell cycle re-entry in AD. Importantly, recent studies indicate that cell cycle re-entry is not a consequence, but rather a cause, of neurodegeneration, suggesting that targeting of cell cycle re-entry may provide an opportunity for therapeutic intervention. Moreover, multiple inducers of cell cycle re-entry and their interactions in AD have been proposed. Here, we review the most recent advances in understanding the pathological implications of cell cycle re-entry in AD.

It was suggested half a century ago that electrical impulses from the lateral hypothalamic area stimulate breathing. It is now emerging that these effects may be mediated, at least in part, by neurons containing orexin neuropeptides (also known as hypocretins). These cells promote wakefulness and consciousness, and their loss results in narcolepsy. Recent data also show that orexin neurons directly project to respiratory centres in the brainstem, which express orexin receptors, and where injection of orexin stimulates breathing. Because orexin neurons receive inputs that signal metabolic, sleep/wake and emotional states, it is tempting to speculate that they may regulate breathing according to these parameters. Knockout of the orexin gene in mice reduces CO2-induced increases in breathing by ∼50% and increases the frequency of spontaneous sleep apneas. The relationship between orexins and breathing may be bidirectional: the rate of breathing controls acid and CO2 levels, and these signals alter the electrical activity of orexin neurons in vitro. Overall, these findings suggest that orexins are important for the regulation of breathing and may potentially play a role in the pathophysiology and medical treatment of respiratory disorders.

Epstein-Barr virus (EBV) is a γ-herpesvirus that infects over 90% of the human population worldwide. It is usually transmitted between individuals in saliva, and establishes replicative infection within the oropharynx as well as life-long latent infection of B cells. Primary EBV infection generally occurs during early childhood and is asymptomatic. If delayed until adolescence or later, it can be associated with the clinical syndrome of infectious mononucleosis (also known as glandular fever or ‘mono%rsquo;), an illness characterised by fevers, pharyngitis, lymphadenopathy and malaise. EBV infection is also associated with the development of EBV-associated lymphoid or epithelial cell malignancies in a small proportion of individuals. This review focuses on primary EBV infection in individuals suffering from infectious mononucleosis. It discusses the mechanism by which EBV establishes infection within its human host and the primary immune response that it elicits. It describes the spectrum of clinical disease that can accompany primary infection and summarises studies that are leading to the development of a vaccine designed to prevent infectious mononucleosis.

Cellular cholesterol homeostasis is a fundamental and highly regulated process. Transcription factors known as sterol regulatory element binding proteins (SREBPs) coordinate the expression of many genes involved in the biosynthesis and uptake of cholesterol. Dysregulation of SREBP activation and cellular lipid accumulation has been associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). This review will provide an overview of ER stress and the UPR as well as cholesterol homeostasis and SREBP regulation, with an emphasis on their interaction and biological relevance.