Drug Discovery Opinion

It has been estimated that as many as 50 million people worldwide suffer from schizophrenia and many of these will be treated with antipsychotic medicines. The so-called typical antipsychotics have been available since the mid-1950s and a number of newer agents, the atypical antipsychotics, have been introduced since 1990. Increased dopaminergic activity is thought to be a contributory factor in schizophrenia and all of the antipsychotic medicines interact with the dopamine D2 receptor although they have different affinities and modulate the receptor in different ways.

A new study has shown that, regardless of their effect on G-protein coupled signalling via the D2 receptor, antipsychotic drugs potently antagonize the dopamine-mediated interaction of the D2 receptor with β-arrestin-2.

Arrestins are proteins that were initially found to regulate signal transduction by silencing GPCRs, although they have recently been shown to directly activate signalling pathways. The new results suggest that selective targeting of the interaction of D2 with β-arrestin-2 may provide a new opportunity for the development of antipsychotic medicines. More generally, targeting β-arrestin signalling pathways may open opportunities in other therapeutic areas.

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Over 150 million people are estimated to be infected with the Hepatitis C virus. During the early stages of infection, the majority of people are free of symptoms but a significant number will later develop cirrhosis and possibly liver cancer.

Treatment is currently a combination of pegylated interferon-α and ribavirin, although several alternative therapies are being developed. Some of the more promising amongst these directly target essential viral enzymes such as the viral protease and polymerase.

The non-structural protein NS4B is an integral membrane protein that also plays a critical role in viral replication.

A new report shows that NS4B binds to viral RNA and describes the use of high-throughput microfluidic screening to identify compounds that inhibit this binding. 18 compounds that substantially reduced NS4B binding to its target RNA were discovered, and one of these compounds, clemizole, was found to inhibit replication of Hepatitis C virus in cell culture whilst showing little cellular toxicity.

Clemizole is an H1 histamine receptor antagonist and, because it has already been tested in people, it could be rapidly evaluated as a treatment for Hepatitis C infection.

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A study carried out in a small group of female students has shown that mental exercise increases food intake. In a ‘within-subjects’ study, each student spent 45 minutes resting, reading a document and writing a summary, or performing a battery of computerised tests. At the end of each 45 minute period, the students were invited to eat as much as they wanted from a buffet.

When the students had been involved in mental activity, they consumed 200 – 250 kilocalories more than when they had been resting. No specific dietary preferences or differences in appetite sensation markers were seen after mental exercise compared with resting. Mean cortisol levels were significantly higher and there was a significant increase in variations in plasma glucose and insulin levels after mental activity. Since the period of mental activity used almost no extra calories compared with resting, this study suggests a new risk factor for positive energy balance with the potential to lead to obesity.

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Whilst moderate exercise in humans appears to enhance immune function and resistance to viral infections, there is evidence that exhausting exercise suppresses the immune response and increases susceptibility to infections.

Intense exercise stress has also been shown to increase susceptibility to upper respiratory tract infection in mice. A new study shows that quercetin can lessen the impact of stressful exercise on the susceptibility to influenza virus A infection in mice.

Quercetin is a naturally occurring flavonol found in many fruits and vegetables, and is known to have antioxidant and anti-inflammatory activity.

A recent study in trained cyclists has also shown that quercetin can help reduce illness and maintain mental alertness in physically stressed human subjects. Although quercetin did not alter several measures of immune function, it did significantly reduce the incidence of upper respiratory tract infections in the cyclists during the 2 week period following intense exercise.

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Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) were developed primarily to treat hypertension, but several recent studies have shown that they could have additional benefits.

In one study, mice in which the gene for ACE had been deleted were found to have lower body weight and a lower proportion of body fat than their wild type litter mates. The decreased body fat in the ACE knock-out mice was independent of food intake and appeared to be due to increased metabolism of fatty acids in the liver, with an additional effect of increased glucose tolerance.

Another study found that use of either ACE inhibitors or Angiotensin Receptor Blockers (ARBs) significantly reduced basal cell carcinoma and squamous cell carcinoma in patients at high risk of these keratinocyte cancers.

High levels of Angiotensin II have also been linked to the pro-angiogenic protein, vascular endothelial growth factor (VEGF) in pancreatic ductal adenocarcinoma (PDA).

An ARB significantly inhibited the Angiotensin II induced increase in VEGF in PDA cell lines and, in an earlier study, an ACE inhibitor was shown to have a similar effect. These studies suggest that ACE inhibitors and ARBs may represent potential novel and promising strategies for controlling angiogenesis, prevention of metastasis, and prolongation of survival in patients with primary or metastatic PDA.

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A recent study suggests that women respond better than men to a commonly used antidepressant medicine, citalopram. The study was designed to compare a large sample of patients in both primary and speciality psychiatric care settings. Although the women had more severe disease at baseline, they responded better to citalopram treatment and experienced more remissions than did the men.

Citalopram belongs to the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). Low serotonin levels are believed to contribute to both mild and severe cases of depression; SSRIs increase serotonin levels at the synapse by blocking reuptake into the presynaptic cell. Citalopram is a racemic mixture; the active S-enantiomer is known as escitalopram.

Although men also benefitted from treatment with citalopram, the authors suggest that the greater response in women may be attributable to sex-specific biological differences, particularly in serotonergic systems. Previous studies have shown that women have lower levels of the serotonin reuptake transporter than men as well as higher levels of the most common serotonin receptor and that there are important differences in the way that men and women react to reductions in serotonin function.

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A recent report suggests that treatment with a combination of two commonly used anti-cancer drugs, doxorubicin and zoledronic acid, may benefit women with breast cancer. Doxorubicin is an anthracycline antibiotic that is widely used in cancer chemotherapy. It is thought to work by intercalating DNA and preventing cell replication.

Zoledronic acid is a third generation bisphosphonate that is used to prevent fractures in cancer patients with bone metastases. The bone destruction associated with malignancy develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The bisphosphonate drugs act by inhibiting osteoclast function.

Zoledronic acid and other bisphosphonates are also used to treat osteoporosis – a single dose of zoledronic acid has been shown to increase bone mineral density for up to a year.

The new study looked at the effects of the two drugs given alone, sequentially , or in combination on the growth of established breast tumours in mice. Alone out of the treatment methods, doxorubicin followed 24 hours later by zoledronic acid almost completely abolished tumor growth in the absence of bone disease. Zoledronic acid has already been shown to reduce the risks of fractures in breast cancer patients with bone metastases and the new study provides hope that new dosing regimens may provide additional benefits.

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Telomeres are repetitive sequences at the 3’-end of DNA which protect the end of the chromosome from destruction during cell division. During the process, the telomeres are themselves destroyed and this mechanism normally limits cells to a fixed number of divisions. Embryonic stem cells express an enzyme, telomerase, which replaces the telomeres and allows the cells to divide repeatedly. Telomerase remains active in some rapidly dividing adult cells, but is switched off almost completely in most other cells to prevent excessive proliferation. Cancer cells often regain telomerase activity and are able to replicate indefinitely. Telomerase activity has been observed in approximately 90% of human tumours and inhibition of this enzyme is seen as a potential treatment for many cancers.

The telomerase is a reverse transcriptase that carries its own RNA primer sequence and has some similarities to the retroviral reverse transcriptases, viral RNA polymerases and B-family DNA polymerases. The first telomerase inhibitor to enter clinical trials for the treatment of cancer is GRN163L, a lipid-conjugated thiophosphoramidate. GRN163L is resistant to nuclease digestion in blood and tissues and has very high affinity and specificity for telomerase.

Small molecule inhibitors such as BIBR1532, which inhibits telomerase activity in vitro with an IC₅₀ in the low nanomolar range, have also been identified. The nucleoside analogue AZT, which is used to treat HIV by inhibiting the viral reverse transcriptase, weakly inhibits telomerase activity.
An advance online publication in the journal Nature describes a high resolution structure of the Tribolium castaneum catalytic subunit of telomerase, TERT (Telomerase Reverse Transcriptase).

It is hoped that the new structure will help in the design of small molecule telomerase inhibitors. As well as de novo design, the similarity between TERT and HIV reverse transcriptase suggests that it may be possible to modify reverse transcriptase inhibitors to inhibit telomerase. Such compounds could potentially be used to treat a wide range of cancers.

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Age-Related Macular Degeneration (AMD) is a condition in which the centre of the retina (the macula) gradually deteriorates, and the detailed vision needed for reading, driving and recognizing faces is lost. There are two types of AMD, a dry form and a wet form: the dry form is more common, but less severe, than the wet form. In the dry form, the cells don’t take in enough vital nutrients and fail to clear cellular by-products so that eventually photoreceptors are lost from the central part of the eye. The wet form is characterised by the growth of new blood vessels which can bleed and leak fluid, leading to scarring and more rapid loss of vision. There is currently no specific treatment for dry AMD, whilst treatment for the wet form involves laser treatment to seal the leaking blood vessels or injection of anti-vascular endothelial growth factor (anti-VEGF) drugs directly into the eye.

A report in the New England Journal of Medicine now warns that a new treatment being developed for the treatment of wet AMD may actually cause harm in patients with the dry form of the disease. The new treatment, which is currently undergoing clinical trials, uses interfering RNA (RNAi) technology to downregulate production of VEGF or VEGF receptors. The new study identifies a link between toll-like receptor 3 (TLR3), which helps the immune system to recognize viral infections, and dry AMD. A mutation associated with low activity of TLR3 appears to offer protection against dry AMD, possibly by suppressing death of retinal cells. The use of RNAi induces TLR3 activation, and so could worsen the prognosis in patients with dry AMD. The discovery also suggests that TLR3 inhibitors may offer a potential new treatment for the more common, dry, form of AMD.

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Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease, diabetes and obesity. A 39-residue synthetic peptide, Exenatide, which is approved for the treatment of type 2 diabetes, acts by mimicking the action of endogenous glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion.

Researchers have now shown that chronic administration of a non-peptide molecule, Boc5, can induce weight loss and increase insulin sensitivity in a mouse model of diabetes and obesity by binding to the receptor for GLP-1. Boc5 is the only non-peptide molecule reported so far that behaves as a full GLP-1 mimetic in vitro and in vivo. Although Boc5 itself does not have the properties of a ‘drug-like’ molecule, it may represent a starting point for the discovery of orally bioavailable agents with the potential to treat metabolic disorders.

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