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Identifying novel small molecule molting regulators for anthelmintic drug development

Award Number: F31AI200475
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/10/2026
PERIOD OF PERFORMANCE END DATE: 12/09/2027

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Identifying novel small molecule molting regulators for anthelmintic drug development - Project Summary/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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,668 )
2026	2026	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Allergy and Infectious Diseases Research	000	1	6/10/2026	NEW	$43,668
														Subtotal = $43,668

Grand Total All Awards = $43,668

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Identifying novel small molecule molting regulators for anthelmintic drug development

Award Number: F31AI200475

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/10/2026

PERIOD OF PERFORMANCE END DATE: 12/09/2027

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