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.
A study published in the July 18th issue of The Lancet shows that a drug once used in Russia to treat hayfever has the potential to improve symptoms in dementia patients. The study of 183 patients, tested dimebon (dimebolin) vs placebo in patients with untreated mild-to-moderate dementia. Patients taking dimebon improved over a six month period whilst those taking placebo got worse.
A smaller group of patients who continued taking dimebon for a further six months showed continuing improvement over this period. This ongoing improvement is seen as particularly important since none of the approved drugs for Alzheimer’s Disease has shown increasing improvement over twelve months. Although this was a relatively small study, the initial results are very encouraging and warrant further investigation.
In a separate study, also reported in The Lancet, immunisation against the amyloid-beta peptide was shown to clear amyloid plaques from the brain, but not to prevent the progressive neurodegeneration associated with Alzheimer’s disease.
Although many companies do not publicise trials, the available evidence shows that biologics are still lagging behind traditional small molecules in the drug development stakes. An analysis published by DrugResearcher of drugs entering clinical trials in 2007 showed that more than twice as many small molecules as biologics made it to first time in man. Although biologics are likely to make up an increasing proportion of new products, there will still be areas where small molecules can achieve better results. Biologics work primarily on disease targets outside the cell, whereas small molecules can also work inside cells. In any therapeutic area, ignoring the intracellular targets may prove costly.