Science Concentrates INFECTIOUS DISEASE
Developing a rapid attack against parasitic worms Preclinical compound targets Wolbachia bacteria that are essential for nematode reproduction C&EN Global Enterp 2019.97:5-5. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 01/17/19. For personal use only.
The parasitic nematode worms responsible for diseases such as river blindness and elephantiasis 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 threadlike worms.
OCH3 OCH3
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Screening hit
AWZ1066S
An academic-industry collaboration called the Anti-Wolbachia Consortium (A-WOL) has now unveiled a preclinical drug candidate that could halt the parasites after a seven-day treatment (Proc. Natl. Acad. Sci. U.S.A. 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 Uni-
versity of Georgia, who was not involved in the research. “This is very good news.” 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 target only 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 life cycle. 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 team then synthesized more
Onchocerca volvulus is a parasitic nematode that causes river blindness. The large worm on the left is a female (coil diameter is roughly 2–3 cm); the smaller is a male. than 300 analogs to improve their potency and speed of action against Wolbachia. Tests on infected mice and gerbils showed that the best compound, called AWZ1066S, virtually eliminated Wolbachia from worms in seven days, clearing the microfilariae from the animals’ blood within 14 weeks. AWZ1066S is water-soluble, is 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. “To my knowledge, there’s nothing else published that has this profile,” Kyle says. 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, says Stephen A. Ward of the Liverpool School of Tropical Medicine, part of A-WOL, adding that they hope to begin a clinical trial by the end of the year.—MARK PEPLOW, special to C&EN
GREENHOUSE GASES
C R E D I T: MA R K TAY LOR / LST M
Rising chloroform emissions traced to China An international team of researchers has reported a surprising rise in global levels of atmospheric chloroform. The study in Nature Geoscience posits that the ozone-depleting substance is coming from eastern China (2018, DOI: 10.1038/s41561-018-0278-2). Atmospheric chloroform can come from both natural sources, such as marine algae, and anthropogenic sources, which mainly include chlorodifluoromethane production and water chlorination. The team found that from 2010 to 2015, global chloroform levels rose at a rate of 3.5% each year, despite being relatively stable or declining in previous decades. They calculated that the increase in emissions de-
tected at measurement stations in South Korea and Japan was similar in magnitude to the global emissions increase and, using models of wind patterns, traced the emissions’ origins back to eastern China, which is highly industrialized. Recently, researchers discovered rogue emissions from east Asia of the banned substance trichlorofluoromethane that may delay ozone recov-
3.5%
The rate of increase per year in global chloroform emissions from 2010 to 2015
ery by a decade. The spike in chloroform emissions could also delay the ozone layer’s recovery by several months or even years if the rate of increase continues. With an atmospheric lifetime of less than six months, chloroform is considered a very short-lived substance (VSLS) and is not regulated by the 1987 Montreal Protocol, the successful global agreement to reduce the emission of ozone-destroying gases. Susann Tegtmeier of the Helmholtz Center for Ocean Research writes in an accompanying review that the findings are “an important step toward opening the discussion of regulating the anthropogenic VSLS emissions.”—TIEN NGUYEN JANUARY 14, 2019 | CEN.ACS.ORG | C&EN
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