Drug Discovery Opinion

Tesofensine is a serotonin-noradrenaline-dopamine re-uptake inhibitor that was originally developed for the treatment of Parkinson’s and Alzheimer’s disease. Although development for these diseases has been discontinued, the discovery that tesofensine caused unintended weight loss in obese patients led to the initiation of new trials for the treatment of obesity. The drug works by suppressing hunger, leading to an energy deficit which burns off excess body fat. Neurosearch, the company that is developing tesofensine, has announced preliminary results from a phase II proof of concept study published online in the Oct 23 edition of the Lancet. The study, which was carried out in five centres in Denmark, involved 203 obese patients with body mass index of 30-40 kg/m² and weighing just over 100kg at the start of the study. The patients ate a limited-energy diet and were assigned to tesofensine (0.25mg, 0.5mg or 1.0mg once daily) or placebo groups for 24 weeks. A total of 161 patients completed the study; mean weight loss for the placebo group was 2.2kg and for the tesofensine groups was 6.7 kg, 11.3 kg, and 12.8 kg (0.25mg, 0.5mg and 1.0mg respectively). For the 0.5 mg and 1.0 mg dose groups, the weight loss was around twice that achieved using sibutramine or rimonabant. The most common side-effects caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhea and insomnia; blood pressure was also increased in the 1.0 mg group.

The study authors conclude that the 0.5 mg dose of tesofensine is more promising than the 1.0 mg dose since it produces a similar weight loss with fewer side-effects, but say that larger phase III trials are needed to substantiate their findings.

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The 2004 film Eternal Sunshine of the Spotless Mind tells the story of a couple who undergo a procedure to erase memories of each other when their relationship turns sour. Now US and Chinese researchers have claimed that they can selectively erase memories from laboratory mice, suggesting that it may one day be possible to erase traumatic memories in people.

The study, which is published in the October 23 issue of the journal Neuron, reveals a mechanism by which both new and old memories can be eliminated without damage to brain cells. Dr Tsien’s group had previously established the role of the NMDA receptor in memory formation. The new study looked at events downstream of the NMDA receptor, and found that over-expression of α-calcium/calmodulin-dependent kinase II (αCaMKII) while a memory was being recalled eliminated that single memory. During memory formation, the NMDA receptor is activated, resulting in the insertion of AMPA receptors into the synapses and subsequent strengthening of synaptic connections. αCaMKII is believed to play an important role in the insertion of AMPA into the synapses during learning and subsequent strengthening of connections between neurons to form a memory. It has previously been very difficult to dissect out the individual components of memory because of the relatively long timescales needed to switch off production of a particular protein. Dr Tsien’s group has now developed a ‘chemical-genetic’ method which means that αCaMKII can be turned on and off instantly in transgenic mice which have been bred to overproduce the molecule. Using this technique, the group were able to selectively erase memories in the mice during the retrieval stage. The team caution that, although the results are very exciting, translation to humans will need much more work.

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The amyloid plaques characteristic of Alzheimer’s disease are made up of small peptides formed by cleavage of amyloid precursor protein (APP). Although the primary function of APP is poorly understood, it is believed to regulate synapse formation and neural plasticity. Synaptic activity of APP involves membrane microdomains containing syntaxin whereas amyloidogenic cleavage occurs primarily in cholesterol-rich lipid raft regions containing one of the proteases needed for APP cleavage, BACE. APP preferentially associates with syntaxin microdomains, but neuronal stimulation causes APP to associate instead with BACE-containing microdomains. It is unclear why this trafficking occurs, but a recently published study in the Journal of Cell Biology showed that movement of APP between the two membrane microdomains is an active process, involving cyclin-dependent kinase 5 (CDK5).

The study also showed that treatment of neurons with the CDK5 inhibitor, roscovitine, which is currently undergoing clinical trials as a treatment for cancer, reduced the association of APP with BACE-rich microdomains, and reduced cleavage.

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The prevalence of asthma is increasing, with up to one in four urban children now affected. Episodes may be triggered by environmental factors, exertion, emotional stress or infection. A recent study by research workers at the University of Texas Southwestern Medical Center, which is available in the Nov 15 issue of the Journal of Infectious Diseases, suggests that infection with respiratory syncytial virus (RSV) may lead to recurrent wheezing, even after the acute symptoms of infection have resolved. The study, which was carried out in mice, showed a striking correlation between the amount of virus detected in the lungs of the mice with the severity of airway hyper-reactivity. The group had previously shown that mice infected with RSV were more likely to develop chronic lung disease than uninfected mice. They also found that treatment of the infected mice with an anti-RSV antibody reduced the amount of virus in the lungs as well as the extent of hyper-reactivity and inflammation in the lungs.

Almost all children have had at least one RSV infection by the age of three, and a study is currently underway to determine whether treating children with an antibody against RSV can prevent wheezing during a one year follow-up period. The findings could lead to the development of treatments for children with recurrent wheezing caused by RSV infection.

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It has been estimated that there are ten times as many bacterial cells as human cells in the body, with the vast majority of bacteria living in the intestine. Around 500 bacterial species are present in the normal human gut and generally provide a beneficial service, synthesizing vitamins such as folic acid, vitamin K and biotin, fermenting complex carbohydrates, and converting lactose to lactic acid. The presence of such bacterial colonies also inhibits the growth of potentially pathogenic bacteria. The microorganisms which populate the gut, termed the commensal microbiotica, are also actively involved in immune regulation and homeostasis and the composition of the microbiota has been suggested to influence susceptibility to inflammatory bowel diseases.

In recent years, IL-17-producing T-helper (Th17) cells have been recognised to be involved in a wide variety of inflammatory conditions and autoimmune diseases. A report in the journal Cell Host and Microbe shows that the small intestine provides an environment that uniquely favours differentiation of Th17 cells which are scarce elsewhere in the body. The composition of the commensal intestinal bacteria was found to have a crucial role in the differentiation of SI LP Th17 cells and in their balance with Treg cells, which also make up a large proportion of CD4+ T cells in the intestinal mucosa. Only a subset of vancomycin-sensitive bacteria were found to induce Th17 cell differentiation, suggesting that unique innate immune signaling pathways, distinct from the TLR-mediated signals that can be initiated by numerous microorganisms, are required for this process. In experiments in mice, the presence of Th17 cells in the mucosa correlated with the presence of members of the cytophaga-flavobacter-bacteroidetes (CFB) phylum, implicating these bacteria as Th17 cell inducers. This is the first report linking a defined set of gut flora to a specific immune response and could help in the development of novel treatments for inflammatory bowel disease and other diseases.

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Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissue most commonly caused by infection with Fonsecaea pedrosoi. The disease occurs most often in rural areas in tropical and subtropical countries and is caused when fungus is introduced by minor injury such as that caused by a splinter or thorn. Chromoblastomycosis is very difficult to cure; antifungal chemotherapy, surgical excision and/or cryosurgery have traditionally been used but with varying degrees of success.

Recently, HIV protease inhibitors have been shown to have a direct effect on AIDS-related opportunistic pathogens such as Candida albicans by inhibiting production of C. albicans secreted aspartyl proteases. The proteases assist the fungus to colonize tissues and to evade the host’s antimicrobial defense mechanisms. F. Pedrosoi also secretes aspartyl proteases and a study published in PloS ONE describes the effect of selected HIV protease inhibitors on secreted protease activity and survival of F. Pedrosoi. At high concentration (100µM), saquinavir and nelfinavir robustly inhibited growth of F. Pedrosoi in vitro. The high concentration needed possibly reflects a much lower affinity for the fungal protease than for HIV protease, or may suggest alternative mechanisms of control. The authors also studied the in vitro effect of combining sub-inhibitory concentrations of the aspartyl protease inhibitors with sub-inhibitory concentrations of antifungal drugs and found good synergistic actions.

The results suggest that combination therapy with protease inhibitors and antimycotic drugs may be effective for treatment of chromoblastomycosis, especially if more potent inhibitors of the F. Pedrosoi aspartyl protease were developed.

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Tuberculosis is a major global cause of death and disease, with around one third of the world’s population believed to be infected with the M. Tuberculosis bacterium. Tuberculosis is known to have infected mankind since ancient times, and a new analysis of bone samples from the now submerged site of Atlit-Yam in the Eastern Mediterranean places the origins of human tuberculosis at least 9000 years ago. The emergence of infectious human diseases has been linked to changes in population density that occurred as a result of moving from a hunter-gatherer lifestyle to settled farming communities. Atlit-Yam is one of the earliest villages with evidence of agriculture and animal husbandry, and is believed to have been submerged shortly after abandonment, thus providing excellent conditions for preservation.

Bone samples from a woman and child, with skeletal changes consistent with a diagnosis of tuberculosis, were examined for evidence of M. Tuberculosis infection. Rigorous precautions were taken to prevent contamination, and independent centres were used to confirm the authenticity of findings. Analysis of DNA and bacterial cell wall lipid biomarkers confirmed that both woman and child had been infected with the modern strain of M. Tuberculosis, with evidence suggesting that the child had been infected shortly after birth. The fact that the 9000-year old samples closely resemble today’s prevalent strains suggests that tuberculosis has infected humans far longer than previously thought.

Since no evidence was found for M. Bovis, the form of the bacterium that infects cattle, the study also supports the current view that M. Tuberculosis did not evolve from M. Bovis.

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Sweet Wormwood (Artemisia annua L) has been used since ancient times in Chinese herbal medicine to treat fever. More recently, the active ingredient, artemisinin, has been used to treat malaria, and herbal extracts have shown activity against some types of cancer.

Researchers at the University of Washington have now found a way to effectively target artemisinin to cancer cells. Artemisinin’s toxicity to cancer cells is linked to the requirement of tumour cells for large concentrations of iron to support rapid cell division.

It is believed that, when artemisinin comes into contact with high iron concentrations, the peroxide bond is reduced, resulting in a cascade that leads to the production of cytotoxic reactive oxygen species. Transferrin is a protein that is involved in the transport of iron into cells and cancer cells express large numbers of transferrin receptors on their surfaces. By linking artemisinin to a peptide recognised by transferrin receptors, the researchers have found a way to enable artemisinin to be co-internalised with iron-carrying transferrin and generate cytotoxic radical species within the cell. Since the mechanism involves a general property of cancer cells, it could form the basis for treatment of a range of different cancers.

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Until very recently, prostatic acid phophatase (PAP) was thought to be a secreted protein found only in the prostate and used as a diagnostic marker for prostate cancer. Little was known about the function of PAP in vivo, or which was its most relevant physiological substrate. The identity of thiamine monophosphatase (TMPase), a classic histochemical marker of small-diameter dorsal root ganglia neurons was also unknown.

An article in the journal Neuron now shows that TMPase is identical to the transmembrane isoform of PAP. The report also describes PAP knockout mice which have enhanced sensitivity in chronic inflammatory and neuropathic pain models. Further evidence of the involvement of PAP in nociception was provided when an intraspinal injection of PAP was shown to suppress pain as effectively as the opioid analgaesic, morphine, but with an effect that lasted much longer (3 days vs 5 hours). PAP suppresses pain by dephosphorylating extracellular adenosine monophosphate (AMP), liberating adenosine which then activates adenosine A1 receptors in dorsal spinal cord. High intrathecal doses of morphine and high doses of A1 receptor agonists cause motor impairment, but no such adverse effects were seen at the highest doses of PAP tested. PAP has a long half life in blood and the present results suggest that PAP is stable in the spinal cord and is capable of generating adenosine for days. The study suggests that modulating the activity of PAP may provide a new option for the treatment of chronic pain.

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Collaborating scientists at the Scripps Research Institute and The Amsterdam Center for Drug Research have determined the crystal structure of the human adenosine A_2A receptor, also known as the caffeine receptor. The receptor is a member of the hetero-trimeric G-protein coupled receptor (GPCR) superfamily and plays an important role in mediating responses to adenosine in many physiological processes. The scientists were able to obtain crystals of the protein by binding it to a potent adenosine antagonist, ZM241385, which had been developed as a potential drug to combat Parkinson’s disease. Full details have been published in the journal Science.

Despite the importance of GPCRs as drug targets, determination of their crystallographic structure has proven difficult. This new structure follows the success of the Scripps team’s publication of the β2-adrenergic receptor structure last year.

Adenosine interacts with a number of GPCRs including the A₁, A_2A, A_2B, and A₃ subtypes. Each of these plays a role in responding to adenosine in the central nervous system in pain regulation, cerebral blood flow, basal ganglia functions, respiration, and sleep. Insights obtained from the study of the A_2A structure have already suggested mechanisms for receptor subtype selectivity.

It is hoped that this new information will help in the design of new drugs that could be important in the treatment of numerous neurological disorders, including Parkinson’s and Huntington disease.

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