10.1371/journal.pntd.0004772
Amruta S. Mhashilkar
Amruta S.
Mhashilkar
Sai L. Vankayala
Sai L.
Vankayala
Canhui Liu
Canhui
Liu
Fiona Kearns
Fiona
Kearns
Priyanka Mehrotra
Priyanka
Mehrotra
George Tzertzinis
George
Tzertzinis
Subba R. Palli
Subba
R. Palli
H. Lee Woodcock
H. Lee
Woodcock
Thomas R. Unnasch
Thomas
R. Unnasch
Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections
Public Library of Science
2016
ecdysone receptor
compound
Filarial Infections Background
filarial parasites
HEK 293 cells
steroidal ecdysone agonists
adult stage parasites
malayi ecdysone receptor
malayi infective larvae
screening results
Ecdysone Hormone Receptor Agonists
2016-06-14 08:33:59
Dataset
https://plos.figshare.com/articles/dataset/Identification_of_Ecdysone_Hormone_Receptor_Agonists_as_a_Therapeutic_Approach_for_Treating_Filarial_Infections/3442502
<div><p>Background</p><p>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.</p><p>Methodology/ Principal Findings</p><p>Administration of 20-hydroxyecdysone to gerbils infected with <i>B</i>. <i>malayi</i> infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the <i>B</i>. <i>malayi</i> 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 <i>B</i>. <i>malayi</i> 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.</p><p>Conclusions</p><p>The studies validate the potential of the <i>B</i>. <i>malayi</i> 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.</p></div>