From engineered fungal molecules to drug leads, chem-bio hybrid synthesis enables antiparasitic drug discovery
Why it matters: This innovative approach offers a path to new, effective, and orally administrable treatments for a prevalent parasitic disease.
- Amebiasis, a parasitic disease affecting 50 million people annually, primarily in tropical and subtropical regions, is the target of this new drug discovery effort.
- Fumagillin and ovalicin, fungal natural products, were identified as potent antiparasitic agents, but ovalicin's rapid breakdown by liver enzymes (CYP 2B1 and CYP 2C6) previously hindered its development.
- Nagoya University scientists, led by Associate Professor Yuta Tsunematsu, engineered fungi to produce modified ovalicin molecules, then chemically customized them to create liver-stable derivatives.
- YOK24 and NS-181, two new compounds, effectively blocked the parasite's MetAP2 enzyme and eliminated parasitic infections in hamsters, even resolving liver abscesses, and were effective via both injection and oral administration.
- Chem-bio hybrid synthesis is introduced as a new drug development method, combining microbial genetic engineering and chemistry to create drug leads that overcome metabolic instability and drug resistance concerns associated with current treatments like metronidazole.
Researchers have developed promising new drug candidates, YOK24 and NS-181, for amebiasis by using a novel chem-bio hybrid synthesis approach to overcome the rapid breakdown of the potent natural product ovalicin by liver enzymes. This method, combining fungal genetic engineering and chemistry, enabled the creation of metabolically stable compounds that successfully cured parasitic infections in animal models, including liver abscesses.
