Grant: Project Grant

Over one quarter of the world's population is infected with a parasitic nematode. These infections result in over 130,000 deaths each year. The world health organization reports that disability caused by nematode infection is equivalent to that caused by malaria or tuberculosis. Resistance to molecules that kill parasitic nematodes is emerging in human infections. Public health experts warn that it is only a matter of time before resistance blooms in nematode parasites of humans. Consequently, public health experts are asking that new nematicidal drugs be developed now. To develop new molecules that kill parasitic nematodes, we screened for small molecules that paralyze and/or kill the tractable, but non-parasitic, nematode C. elegans. We re-screened lethal molecules in human cell culture to eliminate generally toxic molecules. We then screened the remaining molecules against several parasitic nematode species. We identified a small molecule family called 'wact-45' that inhibits the vesicular acetylcholine transporter (VAChT). VAChT functions to package the acetylcholine neurotransmitter within neurons so that they are able to properly communicate with one another. Our data suggests that wact-45 may preferentially inhibit nematode VAChT. We propose to: i) better understand VAChT structure and function, and ii) further develop the wact-45 small molecule structure to optimize its potency and nematode selectivity so that it is safe for use in humans who are infected with nematode parasites. Parasitic nematodes infect vast numbers of people, and especially in poor countries. Children are particularly vulnerable, and infections can lead to disability that lasts a lifetime. Given that resistance to existing anti-nematode drugs is emerging, our work has the potential to lead to new medicines that could have a tremendous global impact on the health of some of the most vulnerable people among us.