Identifying novel small molecule molting regulators for anthelmintic drug development
Active Project Grant Awarded Last action
- Award ID
- F31AI200475
- Recipient
-
University Of California Santa Cruz UEI VXUFPE4MCZH5
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $43,668
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Place of performance
- Santa Cruz, CA 95064, USA
Award details come from USAspending.gov.
Description
- Abstract
- Identifying novel small molecule molting regulators for anthelmintic drug development nuclear hormone receptors (NHRS) are transcription factors that receive a myriad of environmental and developmental signals via small molecule ligand binding, cofactors, and often bind to specific DNA response elements to broadly regulate gene expression across species. NHR-23 is the primary transcriptional driver of the fundamental and conserved process of molting in C. Elegans, making IT an attractive target in anthelmintic drug development. Identifying novel anthelmintic drug targets is essential to combat rising drug resistance to existing treatments. NHR-23 depletion causes molting defects, larval arrest, and even death. However, NHR- 23 is currently considered an "orphan" receptor, meaning the ligand that may bind and regulate its activity is still unknown. Based on the homology of NHR-23 to its mammalian sterol-regulated homolog rorγ, we hypothesize that a small molecule ligand regulates molting through binding to NHR-23. We have already biochemically identified a set of candidate ligands that bind the NHR-23 ligand binding domain, and we have devised a pipeline to functionally screen these ligands in vivo for their effect on developmental rate, molting, physiology, and downstream transcriptional activity of NHR-23 on one target gene, NAS-37. Preliminary data suggest that two bile acids from this candidate set cause severe developmental delay, molting defects, and aberrant cuticle permeability, in addition to altered expression of NAS-37. To further interrogate the binding of ligands to NHR-23 and the effect on its downstream activity, we have taken an interdisciplinary approach combining biochemical and biophysical assays with in vivo genetic manipulation in C. Elegans. Preliminary data suggest that one of our bile acid ligands also binds the brugia malayi NHR-23 ligand-binding domain, enabling US to explore whether the function and ligand signaling through NHR-23 are conserved in this parasitic system. We will elucidate the ligand binding function of NHR-23 through site-directed mutagenesis of the NHR-23 ligand-binding pocket in the C. Elegans and brugia malayi homologs, opening the door to future drug development efforts against this binding and therefore molting in parasitic systems. We further plan to uncover the effect of disrupted NHR-23 ligand binding function on proper molting in C. Elegans using crispr/CAS9 mediated gene editing in vivo. Our work will help identify a bona-fide small molecule molting regulator, developing NHR-23 as a feasible anthelmintic drug target in parasitic nematode infection.
Quick answers
Who received award F31AI200475?
F31AI200475 was awarded to University Of California Santa Cruz by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 10, 2026.
How much is award F31AI200475 worth?
$43,668 has been obligated on F31AI200475.
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