Abstract
To address the cuticular barrier in anthelmintic discovery, this study establishes a bifurcated framework in Caenorhabditis elegans. First, HPLC-based quantification of 14 PIM inhibitors revealed that cuticular penetrance is primarily dictated by phylogenetic lineage (Clade V) rather than ecological niche. Specifically, C. elegans demonstrated a significant pharmacokinetic correlation with the hookworm Ancylostoma ceylanicum (Clade V) but not the whipworm Trichuris muris (Clade I), validating it as a superior surrogate model for hookworm bioaccumulation. Within this small molecule inhibitor library, SGI-12was identified as a lead candidate with superior potency against C. elegans and bioaccumulation. Second, target validation using a C. elegans prk-1; prk-2 double mutant demonstrated that while VB4182 induces spastic paralysis in wild-type nematodes, the kinase-deficient lines exhibit complete phenotypic resistance. Notably, these mutants displayed a constitutive "Long" (Lon) phenotype, suggesting that PRK-1/2 negatively regulate nematode growth. These findings identify PRK-1/2 as the specific in vivo targets of VB4182 and provide a validated methodology to decouple drug permeation from target inhibition in hookworm-targeted drug discovery.
Committee Chair
Makedonka Mitreva
Committee Members
Bruce A. Rosa, Michael Vahey
Degree
Master of Science (MS)
Author's Department
Biomedical Engineering
Document Type
Thesis
Date of Award
Spring 5-2026
Language
English (en)
Recommended Citation
Li, Jiarui, "Establishing Caenorhabditis elegans as a Platform for Bioaccumulation and Selectivity Screening of Anthelmintic Compounds" (2026). McKelvey School of Engineering Theses & Dissertations. 1347.
https://openscholarship.wustl.edu/eng_etds/1347