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Infectious disease

Developing a rapid attack against parasitic worms

Preclinical compound targets Wolbachia bacteria that are essential for nematode reproduction

by Mark Peplow
January 8, 2019 | APPEARED IN VOLUME 97, ISSUE 2

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Credit: Mark Taylor/LSTM
Onchocerca volvulus is a parasitic nematode that causes onchocerciasis (river blindness). The large worm on the left is a female (coil diameter is roughly 2-3 cm), the smaller is a male.

The parasitic nematode worms responsible for diseases such as river blindness and elephantiasis currently infect more than 150 million people in tropical regions around the world. They leave millions of sufferers disfigured and incapacitated, and conventional treatments can take months or even years to kill off the thread-like worms.

An academic-industry consortium has now unveiled a preclinical drug candidate that could halt the parasites after a seven-day treatment (Proc. Natl. Acad. Sci. USA 2019, DOI: 10.1073/pnas.1816585116). “It looks like a much better option,” says parasitologist Dennis Kyle, director of the Center for Tropical and Emerging Global Diseases at the University of Georgia, who was not involved in the research. “This is very good news.”

09702-scicon1-man.jpg
Credit: WHO/Kalapathar Orissa
Lymphatic filariasis (elephantiasis) can cause limb deformities in patients such as this man in India.

Biting insects such as mosquitoes or blackflies can carry worm larvae from person to person, and the adult nematodes can live and reproduce inside their human hosts for years. Current treatments only target immature larvae called microfilariae and leave adults free to reproduce, so long-term treatment programs are needed to clear the worms from patients.

The new drug candidate takes a different approach. It targets a bacterium called Wolbachia that lives inside the worm and is essential for the parasite’s reproduction, although researchers have yet to figure out why. Previous studies have shown that eliminating more than 90% of the Wolbachia can sterilize female parasites and shorten the lives of adult worms, breaking the parasite’s lifecycle.

Antibiotics such as doxycycline can exploit this Achilles’ heel, but it can take up to six weeks of treatment to get rid of Wolbachia, and the antibiotic is unsuitable for children and pregnant women. “You need something that kills the adult relatively quickly,” says Stephen A. Ward of the Liverpool School of Tropical Medicine, part of the Anti-Wolbachia Consortium (A-WOL) that developed the new candidate.

The consortium screened a library of 10,000 compounds for their activity against Wolbachia-infected mosquito cells, and identified a shortlist of 50 active molecules that included a family of promising thienopyrimidines (Science 2017, DOI: 10.1126/sciadv.aao1551). The researchers then synthesized more than 300 analogs to improve their potency and speed of action against Wolbachia.

That eventually led to a champion molecule called AWZ1066S. It contains key chemical groups—including a trifluoromethyl group and a methyl substituent on a morpholine side chain—that make it 10 to 100 times as potent as other analogs. Tests on infected mice and gerbils showed that the compound virtually eliminated Wolbachia from worms in seven days, clearing the microfilariae from the animals’ blood within 14 weeks.

09702-scicon1-awz1066s-new.jpg

AWZ1066S is water-soluble, nontoxic at therapeutic doses, and has good stability against breakdown in the body, making it suitable as an oral drug. It is also highly specific against Wolbachia, so it should not harm essential microbes in human guts. “The key thing is how selective it appears to be,” Kyle says. This combination of fast action, good oral uptake, and selectivity makes it promising, he adds: “To my knowledge, there’s nothing else published that has this profile.”

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A-WOL has developed a low-cost synthesis of the compound’s more active (S)-isomer that takes just five steps from simple starting materials. One of A-WOL’s industry partners Eisai has already scaled this up to 2 kg batches, Ward says, adding that they hope to begin a clinical trial by the end of the year.

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