Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

Authors

Amruta S. Mhashilkar, University of South Florida
Sai L. Vankayala, University of South Florida
Canhui Liu, University of South Florida
Fiona Kearns, University of South Florida
Priyanka Mehrotra, University of South Florida
George Tzertzinis, New England Biolabs
Subba R. Palli, University of KentuckyFollow
H. Lee Woodcock, University of South Florida
Thomas R. Unnasch, University of South Florida

Abstract

Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets.

Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites.

Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites.

Document Type

Article

Publication Date

6-14-2016

Notes/Citation Information

Published in PLOS Neglected Tropical Diseases, v. 10, no. 6, e0004772, p. 1-19.

© 2016 Mhashilkar et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pntd.0004772

Funding Information

The research was supported by a grant from the National Institute of Allergy and Infectious Diseases, USA to TRU (project R21AI103302).

Repository Citation

Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; and Unnasch, Thomas R., "Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections" (2016). Entomology Faculty Publications. 120.
https://uknowledge.uky.edu/entomology_facpub/120