This Small Business Innovation Research (SBIR) Phase I project creates a drug-screening platform for discovery of new antiparasitic drugs. Resistance to current drug treatments is on the rise. New antiparasitic drugs under development are mostly focused on neurotransmission targets, yet a new target has recently emerged, the daf-12 gene. Knudra uses a core expertise in nematode bioengineering to insert parasite genes into the C. elegans roundworm. Drug candidates are found against the parasite gene by the use of biosensor backgrounds, which use fluorescent gene-expression reporters that turn red upon detection of antiparasitic activity. Phase I feasibility is demonstrated when known agonist and antagonist of DAF-12 elicit expected activity on the parasite gene. The platform may then be used to screen compound libraries to find candidates for anthelmintic use.
The broader impact/commercial potential of this project, if successful, will be the creation of a screening platform for finding antiparasitics to help in the battle against important diseases such as elephantiasis, river blindness, trichinosis, Enterobiasis (pinworm), and parasitic infections in livestock and crops. Parasitic infection in livestock and humans currently are treated with more than 20 drugs on the market, but some are toxic and carry black box warnings. Food and health security throughout the world would be enhanced with the development of new antiparasites that are safer and more effective. In addition, the technology will help to bring clarity of understanding to the biology of infective-state formation in parasite lifecycle.
This Phase I SBIR proposal demonstrates a anti-parasite screening platform is feasible for finding drugs against a novel target, the daf-12 gene. The protein made by daf-12 is a nuclear hormone receptor that controls entry into a lifestate for long life in the C elegans nematode. The gene integrates signals from the environment and biosenses when food deprivation is occurring. The gene then turns on a program to convert the nematode into a suspended-animation lifeform that resists harsh environmental conditions. The same gene is involved in detecting when food becomes abundant and then reverses the process, which converts the nematode into reproductive lifeform. Parasitic nematodes us the same pathway to control conversion into and out of parasitic lifestates. A drug that blocks daf-12 signaling for dauer becomes a candidate for controlling parasitic infections. To make a specific drug screening platform the ligand-binding domain of parasite daf-12 genes is swapped for the C. elegans domain. The result is a transgenic animal that uses a parasite protein to detect signals from the environments and control entry into the suspended-animation lifeform. Downstream genes are turned into fluorescent biosensors to detect signaling through the parasite protein. The result is a screening platform for rapid detection of drug candidates for controlling parasite infections. Since the CDC reports one third of the population on the planet is infected with nematode parasites and drug resistance to current treatments is increasing, the development of new anti-parasite drugs is an important task to acomplish.
