Drug Discovery Opinion

There are no medicines that can prevent Alzheimer’s disease and current drugs ease symptoms but do little to stop progression of the disease. There is consequently much current interest in whether lifestyle choices or herbal remedies can prevent or alter the course of Alzheimer’s disease. Two recent reports describe the effect of marijuana-like compounds in elderly rats and extracts of Gingko Biloba in elderly humans.

Previous work has suggested that people who regularly smoked marijuana in the 1960s and 1970s are less likely to develop Alzheimer’s disease in later life. Now scientists at Ohio State University have described details of how constituents of marijuana can combat inflammation and possibly stimulate neurogenesis. The team had found that treatment with WIN-55212-2, a compound with similar pharmacological properties to tetrahydrocannabinol (THC), made a small improvement to the ability of elderly rats to perform memory tests. They then went on to look at how the drug was working, and showed that it lowered inflammation in the hippocampus by acting on the TRPV1 receptor. The team also showed that the action of WIN-55212-2 on CB₁ and CB₂ receptors led to the generation of new brain cells. The group are continuing to investigate which receptors are most important for reducing inflammation and stimulating neurogenesis. This knowledge could lead to the discovery of new drugs to reduce inflammation and increase the production of new neurons before memory loss becomes apparent.

WIN55212-2 is a full agonist at the CB₁ receptor and is not approved as a drug since it elicits cannabis-like effects in humans.

A second report discusses the results of the first randomized, double-blind trial to assess the effectiveness of Ginkgo biloba in reducing the incidence of dementia. Ginkgo is an antioxidant that helps to protect cells in vitro from oxidative damage. Some studies have suggested that ginkgo may also protect against the toxic effects of β-amyloid. Although previous clinical trials of ginkgo leaf extracts have had mixed results, many older people continue to use the herb in the hope of warding off the onset of Alzheimer’s disease. The new study, however, has shown that ginkgo gave no benefit in reducing all-cause dementia or Alzheimer’s dementia. The study involved more than 3000 men and women aged 75 or older who were randomised to placebo or treatment groups. The treated group received 120mg ginkgo twice a day for an average of 6 years. At the end of the study, dementia developed in 246 people taking ginkgo compared with 277 people in the placebo group. The authors note that an effect may have been seen had the study carried on for longer since it is known that there is a significant time lag between initial brain changes and the manifestation of clinical dementia.

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Telomeres are structures which protect chromosomes during cell division and become progressively shorter as a result; telomerase adds telomere DNA to the ends of chromosomes and increases the potential for cell division. Most non-dividing cells show little or no telomerase activity but telomerase is up-regulated in cells that need to divide repeatedly, such as cells of the immune system. CD8⁺ T-cells play a crucial role in controlling HIV infection and, in CD8⁺ T-cells responding to viral antigens, telomerase is up-regulated. During chronic HIV-1 infection, however, CD8⁺ T-cells lose their ability to up-regulate telomerase, leading to critically short telomeres and reduced antiviral activity. A study jointly carried out by scientists at UCLA and the Geron Corporation has shown that TAT2, a small molecule telomerase activator isolated from the Astragalus root, can prevent or slow telomere shortening and increase antiviral efficacy. CD8⁺ T-cells from HIV-infected donors treated with TAT2 showed increased proliferation and enhanced ability to fight HIV.

The study is published in the Nov. 15 edition of the Journal of Immunology.

Although telomerase is up-regulated in cancer cells, TAT2 did not enhance telomerase production by tumour cells. Astragalus is also used in traditional Chinese medicine without obvious side effects suggesting that TAT2 will not promote the development of tumours.

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For many years, it was been believed that we were born with all the brain cells we would ever have, and that new ones could not be formed. More recently, it has been shown that the adult human brain creates new neurons, a process known as neurogenesis. The most active area of neurogenesis is the hippocampus, an area of the brain important for learning and memory. Although the exact role of the newly created neurons is uncertain, to play a part in the acquisition and storage of memories they must locate themselves correctly and be able to communicate with pre-existing circuits in the brain. A new study published in PLoS Biology shows that cyclin-dependent kinase 5 (CDK5) plays a key role in this integration process. The scientists used retroviruses to alter the activity of CDK5, and found that more than 50% of CDK5-deficient cells failed to migrate to the right position in the brain or make the correct connections with surrounding neurons. Instead, the CDK5-deficient cells put out processes in the wrong direction and formed connections with the wrong cells. Cells that fail to integrate correctly could interfere with normal information processing. By increasing understanding of the factors needed for newly formed neurons to become properly integrated into brain, the study may suggest ways to increase the success of neural transplantation to treat brain injuries or diseases such as Parkinson’s disease.

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Human papilloma viruses (HPV) infect the skin and mucous membranes and, although most infections cause no symptoms and are self-limiting, persistent infection can lead to warts or cancer, especially cervical cancer. HPV types are often categorized as ‘low risk’ (causing warts) or ‘high risk’ (causing cancer). Around 30-40 sub-types of the virus are sexually transmitted and the Center for Disease Control estimates that 20 million men and women are infected with HPV. Cervical cancer is estimated to kill almost 4000 women each year in the US, and 300,000 globally.

Two HPV vaccines, Gardasil® and Cervarix®, have recently been introduced to protect women against cervical cancer which is caused primarily by infection with HPV types 16 and 18. Gardasil® additionally offers protection against HPV types 6 and 11 that are most associated with warts.

Newly released results from a phase III study now show that Gardasil® prevented 90% of lesions caused by HPV types 6, 11, 16 and 18 in approximately 4000 men aged 16-26. These are the only data describing the efficacy of an HPV vaccine in preventing disease in men.

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As a target class, kinases have received considerable attention over the last 20 years. There are now 8 kinase inhibitors on the market, approved for use in a number of cancers, with many more in clinical development. Targeting of the catalytic ATP-binding site has proved the most fruitful in drug discovery, but the conserved nature of the site has presented challenges to identification of specific inhibitors. In fact all of the approved compounds inhibit more than one tyrosine kinase, although they maintain selectivity over the serine/threonine and phosphoinositide (PI) kinase classes. This multiple target activity has, however, proven advantageous in an oncology setting.

A collaborative group of researchers has recently reported the identification of dual inhibitors of tyrosine and PI kinases. Their rationale for searching for such compounds was the knowledge that reactivation of PI3 kinase signalling is a common mechanism of resistance to tyrosine kinase inhibitors. Furthermore, preclinical studies combining tyrosine and PI kinase inhibitors have demonstrated efficacy. Despite the sequence dissimilarity between tyrosine and PI kinases, the scientists were able to identify a number of molecules with novel selectivity profiles. In addition, one compound was discovered with unexpected specificity for mTOR compared to other members of the PI kinase family. Full details are reported in Nature Chemical Biology.

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The first cases of severe acute respiratory syndrome (SARS), which is caused by the SARS coronavirus (SARS-CoV), are thought to have occurred in Guangdong province in southern China in November 2002. The virus quickly spread around the globe, with the total number of cases exceeding eight thousand by the summer of 2003. Although this outbreak was contained, the rapid transmission and high mortality rate of SARS prompted an investigation into the viral lifecycle and a search for effective antiviral agents.

A recently published report in the journal PNAS describes the discovery of a potent inhibitor of the SARS coronavirus papain-like protease (PLpro). As well as proteolytic processing of the viral polyprotein, the protease is able to cleave ubiquitin and ISG15 conjugates, and also plays a significant role in allowing the virus to evade the immune system. Optimisation of an initial screening hit led to the identification of a non-covalent inhibitor, GRL0617, which inhibits PLpro with an IC₅₀ of 600nM and inhibits replication of SARS-CoV in Vero E6 cells with an EC₅₀ of 15µM. The X-ray crystallographic structure of GRL0617 bound to PLpro shows the compound binding within the S4-S3 subsites and inducing a loop closure that prevents catalysis at the active site.

Although SARS does not pose a current threat, the identification of GRL0617 shows that inhibition of PLpro is a viable target for the development of antivirals against SARS-CoV.

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In total, around 200million people are thought to be infected hepatitis C virus (HCV). The current standard of care treatment for (HCV) infection is a combination of pegylated interferon, an immune modulator, and ribavirin, an antiviral drug. Interferon/ribavirin therapy is effective in only around 50% of patients with the most difficult-to-treat HCV, type 1. A number of new small molecule antiviral drugs are being developed, and Roche, Pharmasset and InterMune have recently announced the first clinical trial of an interferon-free combination of an HCV NS3/4A protease inhibitor, R7227, and an HCV NS5B polymerase inhibitor prodrug, R7128. Both the protease and polymerase are essential for viral replication and the new study, which will be carried out in Australia and New Zealand, will look at safety and combined antiviral activity of the two compounds in combination.

R7227, which is being developed in collaboration with InterMune, and R7128, which is being developed in collaboration with Pharmasset, have both already successfully completed studies in combination with pegylated interferon and ribavirin.

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The non-structural (NS1) protein of influenza A viruses plays a major role in countering host immune defence by limiting production of interferon and also limiting the antiviral effects of IFN-induced proteins. NS1 also directly modulates stages of the virus replication cycle, including viral RNA replication and viral protein synthesis. Researchers at the Baylor College of Medicine have now identified a mechanism whereby NS1 protein from the highly virulent avian influenza strain, H5N1, ‘hides’ the pieces of double-stranded RNA that would otherwise trigger an antiviral response. NS1 is comprised of two domains: an RNA binding domain and an effector domain. X-ray crystallography of full-length NS1 revealed that molecules of the NS1 protein combine to form tiny tubules which sequester viral RNA. The oligomeric organisation allows the residues involved in RNA-binding to face inwards towards a 20Å wide central tunnel. Binding sites for cellular factors, which may help to evade an immune response, were also identified on the surface of the tubules. It is not yet known whether NS1 proteins from other influenza strains also form similar tubules but, if so, it is possible that the disruption of such structures could form the basis for new treatments. The findings have been reported in the November 5th online edition of the journal, Nature.

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Reoviruses (Respiratory Enteric Orphan virus) are found in sewage and water supplies and, although infection in humans is quite common, most cases do not cause any clinical symptoms and go unnoticed. Over a decade ago, it was discovered that, whilst reoviruses are harmless to normal cells, they selectively kill cancer cells that have a constitutively activated Ras pathway. It is thought that the cycle of infection, replication and cell death is repeated until no cells with an activated Ras pathway remain. Cells with an activated Ras pathway are unable to mount a normal antiviral response mediated by the double-stranded RNA activated protein kinase, PKR. Activating mutations of Ras and mutations along the Ras pathway occur in approximately two-thirds of all tumours.

Now the Canadian company, Oncolytics, have announced that they intend to start a phase II/III study examining the effects of REOLYSIN®, the company’s proprietary formulation of the human reovirus, in combination with paclitaxel/carboplatin in refractory patients with head and neck cancers. In earlier studies, eight out of nine head and neck patients reported on to date had either a partial response or stabilization of disease, a response that exceeds the current standard of care treatment for this patient group. In a separate study, REOLYSIN® was found to be well tolerated and show promise for the treatment of bone/soft tissue sarcoma metastatic to the lung.

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Vascular endothelial growth factor (VEGF) is an important signalling molecule which contributes to angiogenesis. Since angiogenesis is believed to be essential for the growth and metastasis of tumours, blocking the VEGF pathway is considered to be a viable antitumor strategy and both antibodies to VEGF and small molecule inhibitors of VEGF-stimulated tyrosine kinases are used as chemotherapy. Now, a study carried out by researchers at the University of California suggests that dense networks of blood vessels formed during angiogenesis could impede rather than promote the growth of tumours. Inflammatory cells, which infiltrate many tumours, provide a source of VEGF and the team created a strain of mice in which most of the inflammatory cells lacked the gene for VEGF. These mice were then crossed with a strain of mice which reliably develop mammary tumours. Although blood supply to the tumours in the VEGF-deficient mice was reduced, the blood vessels looked more normally organised and less leaky than in the non-engineered mice.

All of the mice developed tumours by 20 weeks of age, but the mice with low levels of VEGF had larger growths that were more likely to have progressed to a later stage of cancer. Although the tumours grew faster in the VEGF-deficient mice, importantly, they were also more susceptible to two different chemotherapy drugs. The study suggests a reason why blocking the effect of VEGF is less effective as monotherapy for cancer than when used in combination with traditional chemotherapy drugs: reduced levels of VEGF lead to more normal blood vessels that are better able to deliver the drugs to the tumour. The findings are published in the 9 November online edition of the journal, Nature.

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