Reducing wriggle room for parasitic flatworms

Thursday, 1 October, 2015
About 300 million people in 75 tropical and sub-tropical countries are infected with Schistosoma flatworms, which cause a debilitating disease. An EU-funded project looked into a new way of fighting the parasites: tackling specific enzymes in the worms to modify gene expression and stop their development in its tracks.

Symptoms of Schistosomiasis – the disease brought about by schistosomes in human hosts – include abdominal pain, diarrhoea, and bloody stool/urine. The illness can ultimately lead to liver damage, kidney failure, infertility or bladder cancer. Some 300 000 carriers die from symptoms directly related to the disease every year. The main group affected by the parasite is young children.

Only one drug is currently on the market to combat schistosome infections, and it is being used in a mass treatment campaign targeting school-aged children in sub-Saharan Africa. While this treatment is clearly having an impact on the symptoms of the disease, its transmission continues unhindered. What is more, the mass use of the drug may induce resistance in the parasite sooner rather than later, so researchers are urgently searching for new drug candidates.

The SEtTReND project chose histone-modifying enzymes (HMEs) as the point of attack. Histones are the specific proteins that make up the chromatin, a complex of molecules into which the DNA is packaged tightly so that it fits in the cell. Chromatin controls gene expression and DNA replication, among other things.

Inhibiting HMEs will lead to changes in chromatin structure that will affect gene expression, i.e. the interpretation of the information stored in our genes. In this case it would disturb the flatworms’ natural development, and cause cell death and death of the parasites.

Piggybacking on other research

“These enzymes are heavily targeted, notably in cancer research,” explains Raymond Pierce, who coordinated the SEtTReND project on behalf of the French Institute of Health and Medical Research (INSERM). “We can tap into the information about compounds that are being developed as drugs against cancer and piggyback on the knowledge to try the compounds against parasites.”

While studying several potential targets, the team identified one particularly promising candidate called histone deacetylase 8 (SmHDAC8) in the species Schistosoma mansoni. SEtTReND showed that it is a valid target: in a mouse model of the disease, inhibiting SmHDAC8 prevented the development of the larvae into adult worms and efficiently killed the parasite.

Detailed analysis of the enzyme’s structure yielded more good news: “All these enzymes have their counterparts in humans. If you produce a drug targeting the schistosome enzyme, ideally you want it not to be terribly active against the human enzyme to avoid side-effects,” says Pierce. “We were able to show that there were crucial differences between the Schistosome enzyme and the human one.”

What is more, the catalytic pocket, i.e. the business end of the enzyme, has the same structure in two other Schistosome species – Schistosoma haematobium and japonicum – as well as parasitic flatworms of other families. Therefore, any drug developed against S. mansoni should also work on the other parasites.

Feeding the drug pipeline

The drug development process up until actual approval for humans is a long and arduous one. The hunt for novel Schistosomiasis drug targets therefore continues: the original SEtTReND consortium has joined forces with numerous new partners. The A-PARADDISE project – also funded by the EU – is pursuing the same strategy, but has expanded to other kinds of parasites, including those causing Malaria and Leishmaniasis.

“I hope that at the end of the A-PARADDISE project, we will have compounds that are active in animal models and have adequate pharmacokinetic properties to go forward with the tests,” says Pierce. “This may take 10 years – if any compounds make it through the entire process. However, we have to do this now, because 10 years down the line, today’s drugs may be completely unusable. For a lot of these diseases, we know they will be. This is why we have to feed the drug pipeline.”

Schistosoma Epigenetics - Targets, Regulation, New Drugs
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