Drug Discovery Opinion

Alzheimer’s disease is characterised by the presence of neurofibrillary tangles and deposits of amyloid peptides (Aβ) in the brain. N-terminally truncated and pyroglutamate-modified Aβ peptides (Aβ_(pE)) are resistant to proteolysis, aggregate more readily than the unmodified peptides, and have been implicated in the initiation of events leading to the development of Alzheimer’s disease. In post mortem examinations, brains from Alzheimer’s patients were found to contain significantly larger amounts of pyroglutamate-modified peptides than brains from aged controls. Aβ_3(pE)-42, particularly, is a major component of Aβ deposits in both familial and sporadic Alzheimer’s disease.

A recent letter to the journal Nature identifies glutaminyl cyclase as the enzyme which catalyses the N-terminal pyroglutamate formation in vivo. Glutaminyl cyclise protein and mRNA were found to be up-regulated in Alzheimer’s disease patients and significantly larger concentrations of Aβ_3(pE)-42 were also detected. In HEK cells co-expressing amyloid precursor protein (APP) and glutaminyl cyclise, formation of Aβ_3(pE)-42 was suppressed by the glutaminyl cyclase inhibitor, PBD150. Different studies looking at the effect of oral dosing of PBD150 to transgenic mice over 3, 6 or 10 months showed dose-dependent decreases in Aβ_3(pE)-42 and reduced de novo plaque formation. Transgenic mice treated with PBD150 also showed improved memory as determined by a conditioned fear procedure.

The results suggest that formation of Aβ_3(pE)-42 can be reduced by inhibition of glutaminyl cyclise without any effect on previously formed deposits and provide evidence that Aβ_3(pE)-42 can act as a seed for aggregation. If inhibition of glutaminyl cyclise is similarly effective in humans, this could provide a new approach to disease-modifying treatment for Alzheimer’s disease.

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Two new analyses by Cochrane researchers suggest that honey may be more effective than conventional dressings as a topical treatment for burns. The first analysis looked at the results of 19 randomised or quasi-randomised studies that evaluated honey as a treatment for any sort of acute or chronic wound. Although all of the burns trials were carried out at a single centre, the authors concluded that honey may improve healing times in mild to moderate superficial and partial thickness burns compared with some conventional dressings.

A second analysis looked at data from 26 randomised controlled trials that evaluated the effects of burn wound dressings for superficial and partial thickness burns. Although most of the studies were considered to be methodologically poor, the use of silver sulphadiazine (SSD) bandages was found to be associated with delays in wound healing and increased numbers of dressing applications.

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A recently published cross -sectional study of almost 1500 people has demonstrated an association between higher urinary bisphenol A (BPA) concentrations and increased risk of cardiovascular disease and diabetes, as well as abnormally high levels of some liver enzymes.

Now, a new study has shown that low nanomolar concentrations of BPA antagonise the cytotoxic effect of the chemotherapeutic agents doxorubicin, cisplatin and, to a lesser extent, vinblastine in both oestrogen receptor α positive and negative breast cancer cells, possibly by increasing expression of anti-apoptotic Bcl-2 proteins.

Both of these studies add to the growing evidence for detrimental effects of BPA on human health.

BPA is widely used in epoxy resins lining food and drink containers and as a monomer in polycarbonate plastics used in many consumer products. Previous evidence of adverse effects in animals has generated concern about the effect of low level exposure in humans. Most studies have concentrated on the well-documented oestrogenic activity of BPA but these new studies suggest other possible detrimental effects.

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Extracts of the plant Hypericum perforatum L. (St. John’s wort) have traditionally been used in folk medicine to treat a range of disorders, including mental disorders and nerve pain. The common name, St John’s Wort, derives from its traditional flowering and harvesting on the feast of St John the Baptist in late June.

A newly published meta analysis of the effectiveness of extracts of Hypericum perforatum in treating patients with symptoms of depression has concluded that the extracts are more effective than placebo and are as effective as standard antidepressants with fewer side effects. The study analysed results from 29 randomised, double blind trials (5489 patients) comparing extracts of St. John’s wort with placebo or standard antidepressants on clinical outcomes assessing depressive symptoms. The herbal extracts were found to be as effective as tricyclic or tetracyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). The original studies were carried out in a number of different countries and it is interesting to note that extracts of St. John’s wort appeared to be considerably more effective in German-speaking countries. Hypericum contains a number of compounds that could contribute to its pharmacological activity and its precise mechanism of action is unclear.

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The human immunodeficiency virus (HIV) uses host cell surface receptors such as CD4, CCR5 and CXCR4 to gain entry into cells. Recently, monoclonal antibodies and small molecules that block these receptors have joined the armoury of drugs used to combat HIV infection. A new report in the journal Cell describes a genome-wide analysis to search for other virus-host interactions that are important for the early steps of HIV infection.

More than 40 host factors that regulate capsid uncoating and reverse transcription were identified along with 15 cellular factors that facilitate entry of the HIV preintegration complex into the cell nucleus and integration of proviral DNA.

Cytoskeletal proteins and microtubules were found to play roles in early HIV replication, and proteins involved in DNA-damage repair were found to influence the initiation of reverse transcription and the accumulation of HIV-1 DNA products prior to integration. Other cellular systems discovered to play roles in the early stages of HIV infection include nucleic acid binding proteins and the ubiquitin-proteasome pathway. Protein phosphorylation and dephosphorylation events were found to have a possible role in the regulation of HIV-1 reverse transcription, and prostaglandins were shown to have a potential role in HIV-1 nuclear import. Several cellular factors were also found to be important for HIV-1 DNA integration.

The study revealed totally new pathways in HIV infection, including involvement of Notch signalling in reverse transcription. A full understanding of the role of each of these host factors in cell types infected by HIV will be essential to assess their contribution to disease progression. However, given the success of compounds which block viral entry receptors, modulation of the activity of some of the newly discovered pathways could provide novel strategies for the treatment of HIV/AIDS.

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Although many individuals colonised with H. pylori remain asymptomatic, some develop stomach or duodenal ulcers or stomach cancer. Once an almost universal human pathogen, advances in sanitation and use of antibiotics have significantly reduced the prevalence of the bacterium, especially in Western counties. The decline in H. Pylori colonisation has been accompanied by a decline in the incidence of gastric cancer. In contrast, the number of cases of oesophageal adenocarcinoma (EAC) has increased sharply over a similar timescale. Worldwide, most cases of oesophageal cancer are oesophageal squamous cell carcinoma (ESCC), especially in high risk areas such as China and Iraq. In some Western countries such as the United States and the United Kingdom, however, approximately half of all cases of oesophageal cancer are EAC.

A new meta-analysis has examined the association between H. Pylori and oesophageal cancer. The results suggest that the risk of EAC, but not ESCC, is reduced in individuals colonised by the predominant CagA-positive strain of H. Pylori. The low rates of EAC in developing countries, where H. pylori is still common, are consistent with the hypothesis that decreased prevalence is contributing to the observed increase in incidence of EAC.

H. pylori may protect against EAC by reducing acid reflux to the oesophagus, and by reducing production of the hormone ghrelin which in turn may lead to lower incidence of obesity, an important risk factor for EAC. The protective association of H. pylori with EAC may also be part of a wider beneficial effect of H. pylori colonisation that has developed over many years of co-existence. Other important risk factors for EAC are gastroesophageal reflux, obesity, and smoking.

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Progeria is a very rare genetic disease characterised by dramatic premature ageing; Hutchinson-Gilford progeria syndrome (HGPS) is the most severe form of the disease. As newborns, children with progeria usually appear normal but, within one year, their growth rate declines. The children develop a distinctive appearance with alopecia, a small face and jaw and a pinched nose. They have small fragile bodies like those of elderly people and suffer symptoms typically associated with ageing, including joint stiffness and severe progressive cardiovascular disease. Affected children usually die in their early teens from complications of atherosclerosis such as heart attack or stroke.

Little research was carried out into the disease until the 1990s but it is now known that HGPS is caused by a mutation in the LMNA gene which encodes the nuclear membrane protein lamin A. Lamin A requires posttranslational farnesylation to be incorporated into the nuclear membrane; the C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold, affecting nuclear structure and function.
Farnesyl transferase inhibitors (FTIs), originally developed as anticancer drugs, have been shown to reduce disease significantly in animal models of HGPS. A phase II clinical trial using the FTI lonafarnib began in May 2007 and has an estimated completion date of October 2009.

A new study published in the Proceedings of the National Academy of Sciences describes the effect of another FTI, tipifarnib, in transgenic mice that develop cardiovascular disease similar to that seen in progeria patients. Tipifarnib was able to prevent, and even reverse, the cardiovascular damage in mice, giving hope that a similar effect will be seen in the patients treated with lonafarnib.

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Vitamin C is an essential nutrient that can be synthesised by most organisms, with humans being the most well-known exception. Although the health benefits of eating fruits and vegetables are well recognized, optimal daily intake of vitamin C is still the subject of much on-going debate.

A new study in leukemia and lymphoma cell lines has shown that pretreatment with vitamin C dose-dependently reduces the effectiveness of the widely used but mechanistically dissimilar cancer drugs, doxorubicin, cisplatin, vincristine, methotrexate, and imatinib. A similar effect was seen in mice with RL cell–derived xenogeneic tumours, when vitamin C significantly reduced the effectiveness of doxorubicin in preventing growth of the tumours. All of the drugs used in the study cause depolarization of the mitochondrial membrane in the tumour cells which leads to cell death. This mitochondrial damage was inhibited in the presence of vitamin C, and probably explains why the drugs were less effective.

Although this study suggests that use of vitamin C supplements during cancer treatment may limit the effectiveness of chemotherapy, it is difficult to know what dose of vitamin C would be detrimental in patients.

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Statins inhibit HMG-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis, and are used to lower cholesterol levels in patients with, or at risk of, cardiovascular disease. In addition to reducing cholesterol levels, statins have also been shown to have direct effects on cells of the blood vessel walls. In patients with atherosclerosis, vascular smooth muscle cells show evidence of DNA damage and ‘premature ageing’.

A new study has identified a novel mechanism, involving Nijmegen breakage syndrome (NBS)-1 protein and the human double minute protein Hdm2, by which statins are able to accelerate DNA repair. This means that, in addition to their beneficial effect on cholesterol levels, statins are also able to slow the ageing process in the diseased arteries.

Statins can also reduce DNA damage caused by ionizing radiation or cytotoxic drugs and could be useful as an adjunct to cancer treatment.

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The term “Acquired Immunodeficiency Syndrome” or “AIDS” was first coined in 1982 to describe a newly recognised set of unexplained symptoms that occurred most frequently in gay men. In 1984, the cause of this disease was found to be a virus, now universally known as the human immunodeficiency virus, HIV. It is estimated that 25 million people have died as a result of AIDS and, that in 2007, around 33 million people were infected with the virus.

It had been thought that HIV transferred to humans in the 1930s, but a new study published in the journal Nature suggests that the virus crossed species much earlier. Comparison of the genetic differences between a sample of HIV obtained from human tissue in 1960 with an older sample obtained in 1959 suggests that a common ancestor had infected humans around 1900. The rise and growth of cities in west-central Africa in the late 19^th and early 20^th centuries may have been a contributing factor to the spread of the virus once it had crossed into the human population.

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