Onchoceriasis – also known as river blindness – is the world’s second leading infectious cause of blindness. The disease is caused by the nematode, Onchocerca volvulus, and is transmitted to humans through the bite of a blackfly. Once inside the body, the female worm produces thousands of larval worms (microfilariae) which migrate to the skin and eyes. When the microfilariae die, they cause intense itching and a strong immune response that can destroy nearby tissue, leading eventually to blindness and disfiguring skin lesions. Control programmes have involved the use of larvicides to reduce blackfly populations and the use of ivermectin to treat infected people and limit the spread of disease. Ivermectin is most effective against the larval stage of the worm and is believed to kill the parasites by activating glutamate-gated chloride channels which are specific to invertebrates.

A team led by researchers at the Scripps Institute has now focused on a new way to kill the parasite. The protective outer cuticle of the worms is made of chitin and two classes of enzymes – chitin synthases and chitinases – are known to be critical for chitin formation and remodelling. One chitinase, OvCHT1, is expressed only in the infective third-stage larvae and is believed to be involved in development and host transmission. The team screened a small library of compounds for activity against OvCHT1 and found that closantel was able to inhibit the enzyme. When closantel was tested on cultured third-stage larvae, the compound prevented the larvae from moulting and developing into adult worms. Since the mechanism of action of closantel is completely different to that of ivermectin, it – or other chitinase inhibitors – could potentially be used to treat ivermectin-resistant worms. Closantel is a broad-spectrum anti-parasitic agent currently used in some countries in veterinary medicine.

The study is published in the Proceedings of the National Academy of Sciences.

In 2008, researchers led by a team at Columbia University showed that, by turning on or off production of serotonin in the gut, they could control bone formation. Serotonin signals to cells in the skeleton to slow production of new bone and, by turning off the intestine’s release of serotonin, the team was able to prevent osteoporosis in mice undergoing menopause. The team have now shown that daily oral administration of LP-533401 for 6 weeks is effective both prophylactically and therapeutically against osteoporosis in ovariectomized mice.

LP-533401 inhibits tryptophan hydroxylase-1 (TPH-1), the first enzyme in gut-derived serotonin biosynthesis. TPH-1 is mostly expressed in peripheral tissues such as the gut, whilst TPH-2 is the major isoform in the central nervous system. Although LP-533401 inhibits human TPH-1 and TPH-2 with similar potency (K_i ~ 0.7µM) in vitro, it selectively lowers serotonin levels in the gut whilst leaving levels in the brain unchanged, likely because the compound does not cross the blood-brain barrier. LP-533401 and an ethyl ester pro-drug were originally developed to treat gastrointestinal diseases such as irritable bowel syndrome and to reduce chemotherapy-induced vomiting and nausea.

Although much work will need to be done before trials can be carried out in patients, the present study, which is published in Nature Medicine, demonstrates that pharmacological inhibition of synthesis of gut-derived serotonin could become a new anabolic treatment for osteoporosis. Most osteoporosis drugs only prevent the breakdown of old bone and are not able to stimulate the growth of new bone.

Although a variety of broad-spectrum antibiotics have been developed, broad-spectrum antiviral agents have proved more difficult to identify. Effective treatments have been developed for individual viruses such as HIV, herpes viruses and influenza viruses – and vaccines have also been developed against papilloma viruses and herpes viruses – but there is a need for small molecules that are able to treat a range of viral infections and could also be used against newly emerging viruses.

Researchers led by a team at UCLA have now identified a compound, LJ-001, that can treat a range of enveloped viruses. The team screened a library of around 30,000 compounds against Nipah virus, a pathogen that was first identified in 1998 and causes severe disease in both animals and humans. Further tests showed that LJ-001 was also effective against other enveloped viruses including Ebola virus, HIV, hepatitis C virus, West Nile virus, Rift Valley fever virus, yellow fever virus and influenza A virus, but had no effect against non-enveloped viruses. The compound interacts with the viral lipid envelope and inhibits viral entry at a step after virus binding but before virus–cell fusion.

Although LJ-001 also binds to cellular membranes, the team believe that its low toxicity can be attributed to the fact that metabolically active cells are able to repair their membranes whilst static viruses are not. LJ-001showed no overt toxicity at effective anti-viral concentrations in either in vitro or in vivo studies, and pretreatment of mice with LJ-001 prevented virus-induced mortality from Ebola and Rift Valley fever viruses.

The study is published in Proceedings of the National Academy of Sciences.

Roles have been suggested for brain-derived neurotrophic factor (BDNF) – which helps to support neurons and also stimulates and controls neurogenesis – in preventing or treating degenerative diseases such amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. The use of BDNF itself in therapy is limited by a poor pharmokinetic profile including rapid metabolism and poor CNS penetration. BDNF elicits at least some of its effects through binding to the high affinity tyrosine kinase receptor B, TrkB, and investigators at Emory University School of Medicine have now identified a small, high-affinity molecule that can also activate signalling through TrkB.

7,8-Dihydroxyflavone was shown to protect wild-type, but not TrkB-deficient, neurons from apoptosis. Following intraperitoneal administration, the compound was also found to activate TrkB in the brain and to be protective in animal models of seizure, stroke and Parkinson’s disease. The compound was also found to have low toxicity on chronic dosing. Although favonoids such as 7,8-dihydroxyflavone occur in a wide range of foodstuffs, levels obtained from a normal diet are believed to be insufficient for a sustained effect.

The study is published in the online early edition of PNAS.

Neurons are particularly sensitive to the toxic effects of misfolded proteins and the accumulation of such species has been associated with neurodegenerative diseases including Parkinson’s disease, amyotropic lateral sclerosis (ALS), Alzheimer’s disease and transmissible spongiform encephalopathies (prion diseases). Hereditary protein conformational disorders such as Huntington’s disease are characterised by trinucleotide repeats that result in the insertion of poly-glutamine (polyQ) stretches which adopt β-sheet structures and make the protein prone to incorrect folding and aggregation. The ability to stabilise native protein conformations would likely prevent the neurotoxicity linked to misfolding and scientists at Duke University Medical Center have now discovered compounds that may be able to achieve this.

Since increasing the levels of protein chaperones has been shown to suppress protein misfolding, the team focussed on identifying small molecule activators of heat shock transcription factor 1 (HSF1), the master regulator of protein chaperone gene transcription. HSF1A was discovered using a humanised yeast-based high throughput screen and shown to activate HSF1 in mammalian and fruit fly cells, to elevate protein chaperone expression, and to reduce protein misfolding. HSF1A was also shown to prevent cell death in polyQ-expressing neuronal precursor cells and to protect against cytotoxicity in a fruit fly model of polyQ-mediated neurodegeneration.

Previous screens that have identified activators of HSF1 have not been able to discriminate against compounds that promote HSF1 activation through the proteotoxic accumulation of unfolded proteins or through the inhibition of Hsp90, a central chaperone involved in cell growth, signalling, and proliferation. HSF1A is structurally distinct from other small molecule activators of HSF1 and, although the precise mechanism by which the compound activates human HSF1 is not yet understood, it could lead to new therapies for neurodegenerative diseases caused by protein misfolding.

The study is published in PLoS Biology.

The lower alcohol tolerance of some Asian groups compared with people of European descent is caused, in part, by a mutant copy of the aldehyde dehydrogenase gene, ALDH2. As well as carrying out the second step in the oxidative metabolism of alcohol, the conversion of acetaldehyde to acetic acid, ALDH2 metabolises toxic species created by lack of oxygen in the wake of a heart attack and is involved in the metabolism of nitroglycerine which is used to treat angina. People with a deficiency in the activity of ALDH2 are at increased risk of cardiovascular damage and scientists at Indiana University and Stanford University reported in 2008 that a small molecule activator of ALDH2, Alda-1, could reduce infarct size in rats if administered before ischaemic damage. In vitro, Alda-1 was found to be a particularly effective activator of the inactive form of the enzyme found in some East Asian populations, suggesting that treatment with Alda-1 could be of benefit to individuals with either wild-type or mutant ALDH2 who are subjected to cardiac ischaemia by a heart attack or by procedures such as coronary bypass surgery.

Writing in Nature Structural & Molecular Biology, the team have now described mechanistic details of the activation of ALDH2 by Alda-1, a discovery which should lead to more potent and selective analogues of Alda-1 with better promise as drug candidates to minimize ischaemic heart damage. The structures of bound Alda-1 reveal how the compound activates the wild-type enzyme and how it restores the activity of the inactive form by acting as a structural chaperone.

The cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction and selective inhibitors of the different subtypes have great clinical potential. PDE4 inhibitors are expected to be beneficial in the treatment of inflammatory and respiratory diseases such as asthma and COPD as well as CNS disorders including schizophrenia, depression, and Alzheimer’s disease but their potential has so far been limited by the incidence of side effects, particularly emesis. The emetic response is mediated in part by a brainstem noradrenergic pathway and, for non-CNS indications, can be reduced by limiting distribution of inhibitors to the brain. Active site directed PDE4 inhibitors completely inhibit enzyme activity at high concentrations but researchers at Emerald Biostructures (formerly deCODE biostructures) have now identified allosteric small molecule modulators of PDE4 with reduced potential for side effects. The four PDE4 variants (PDE4A, B, C, and D) all contain signature regulatory domains called upstream conserved regions 1 and 2 (UCR1 and UCR2). UCR2 is needed for high-affinity binding of the PDE4 inhibitor rolipram and X-ray crystallographic structures revealed that small molecule inhibitors bind to UCR2, thereby controlling access to the active site. The team used the structural data together with supporting mutational data to design PDE4 allosteric modulators that only partially inhibit cAMP hydrolysis. The modulators were shown to be potent in cellular assays as well as in vivo cognition tests and to have greatly reduced potential for emesis in several species. The authors hope that their work will lead to the identification of PDE4 modulators with reduced potential for emesis that can be used to treat disorders where brain distribution is needed. The study is published in the December 27^th advance online issue of Nature Biotechnology.

Kaposi’s sarcoma (KS) is caused by Kaposi sarcoma herpes virus (KSHV) which is also known as human herpes virus 8 (HHV8). HHV8 infection rates vary widely amongst different populations but KS rarely develops unless the immune system is compromised, by AIDS, transplant drugs, or ageing. There is currently no specific treatment for KS but researchers at UCSF have now identified small molecules that target the viral protease. Along with other members of the herpes family of viruses – including herpes simplex viruses I and II, varicella zoster virus, cytomegalovirus and Epstein-Barr virus – HHV8 encodes a serine protease that is essential for viral capsid formation and viral replication. Many previous attempts to discover inhibitors of herpes virus proteases targeting the active site of the enzymes met with limited success, perhaps because of difficulty in finding molecules that bind tightly to the shallow substrate-binding cleft. The UCSF team have chosen instead to inhibit catalytic activity by disrupting dimerisation of the enzyme.

A number of earlier studies have shown that dimerisation is a common mechanism for activation of herpes virus proteases, and the UCSF team have previously identified a helical peptide that prevents dimerisation of herpes virus proteases. In the new study, published online in the journal Nature Chemical Biology, the team describe small molecules, including DD2, which inhibit dimerisation of both HHV8 and CMV proteases with IC₅₀s in the low micromolar range.

HIV protease also acts as an obligate dimer but, in this case, dimerisation inhibitors have been less successful than compounds that directly target the active site, many of which are now in clinical use. The difficulties experienced in trying to identify active site inhibitors of the herpes virus serine proteases may mean that disruption of dimerisation presents a more attractive target for these challenging enzymes.

Cystic fibrosis (CF) is a hereditary disease characterised by the production of thick sticky mucus which results in frequent lung infections. CF is caused by any one of a number of mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR) which encodes a protein that transports chloride ions across cell membranes. In about 10% of patients worldwide, and more than 50% of patients in Israel, CF is caused by nonsense mutations in the messenger RNA for CFTR. Premature stop codons prevent production of functional full-length protein: patients with nonsense-mutation CF produce very little functional CFTR and often have a severe form of CF.

New Phase II results published in The Lancet show that an orally bioavailable small molecule demonstrates activity in nonsense-mutation CF. PTC124 was designed to induce ribosomes to selectively read through premature stop codons to produce functional CFTR. The data show that treatment with PTC124 results in statistically significant improvements in the chloride channel function of patients.

Nonsense mutations account for a significant number of cases of most inherited diseases and PTC124 may have the potential to treat diseases other than CF.

Prostate cancer is the most common cancer among men, and it has been estimated that up to 10,000 men in the UK are diagnosed each year with the most aggressive form of the disease. A small scale clinical trial has now shown that abiraterone is able to shrink prostate cancer tumours in patients who have not responded to alternative medical or surgical treatments. Abiraterone works by inhibiting production of male hormones, which can stimulate the growth of prostate cancer cells, throughout the body and not just in the testes.

Many of men on the trial reported significant improvements in their quality of life and some were able to stop taking morphine for control of pain caused by the cancer spreading into their bones.