Development of Inhibitors of the Nuclear Receptor DAF-12 to treat parasitic diseases – DIN-R

The global prevalence of nematode infections in humans and animals causes severe diseases and agricultural losses, posing substantial health and economic challenges. Current treatments are based on anthelmintic drugs, whose effectiveness is increasingly compromised by the emergence of drug resistance, with no alternatives expected soon. Nuclear receptors, key transcription factors regulating metabolic and developmental networks, are found across all helminth species but remain understudied in parasitic nematodes. The project focuses on DAF-12, a nuclear receptor that regulates the infective larval stage in several nematodes. Inhibiting DAF-12 would block larval development and prevent parasites from settling in their host, making it a promising therapeutic target distinct from current anthelmintic approaches. The project is an interdisciplinary collaboration integrating expertise in biochemistry, structural biology, chemical biology, pharmacology and parasitology. It is based on our discovery of a short peptide binding with high specificity and affinity to DAF-12 from several parasitic nematodes, that will serve as a lead compound for the development of DAF-12 inhibitors. The main goals of the project are (1) to optimize and characterize the functional/pharmacological properties of peptides derived from the initial one to block the essential interaction between DAF-12 and transcriptional coregulators, (2) to develop DAF-12 degraders using the PROTAC technology where a bifunctional ligand directs the protein to degradation, and (3) to demonstrate the efficacy of these compounds in blocking parasitic nematode infections. The data obtained at atomic, cellular and living organism levels will shed new light on DAF-12’s role in nematode development, and promise substantial progress in innovative therapeutic strategies to combat parasitic infections in humans and animals, addressing the urgent need for next-generation antiparasitic therapies.