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



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.



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.
Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America.
Amruta S
AS
Mhashilkar
Department of Chemistry, University of South Florida, Tampa, Florida, United States of America.
Sai L
SL
Vankayala
Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America.
Canhui
C
Liu
Department of Chemistry, University of South Florida, Tampa, Florida, United States of America.
Fiona
F
Kearns
Department of Chemistry, University of South Florida, Tampa, Florida, United States of America.
Priyanka
P
Mehrotra
New England Biolabs, Ipswich, Massachusetts, United States of America.
George
G
Tzertzinis
Department of Entomology, University of Kentucky, Lexington, Kentucky, United States of America.
Subba R
SR
Palli
Department of Chemistry, University of South Florida, Tampa, Florida, United States of America.
H Lee
HL
Woodcock
Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America.
Thomas R
TR
Unnasch
D000599:Amino Acids, Diamino / Q000008:administration & dosage; D000818:Animals; D017178:Brugia malayi / Q000187:drug effects / Q000302:isolation & purification; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004440:Ecdysone / Q000378:metabolism*; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005368:Filariasis / Q000188:drug therapy* / Q000469:parasitology; D005849:Gerbillinae; D057809:HEK293 Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011987:Receptors, Steroid / Q000819:agonists* / Q000378:metabolism
D000599:Amino Acids, Diamino; D006834:Hydrazines; D008024:Ligands; D011987:Receptors, Steroid; C055469:ecdysone receptor; C121557:hydroxyectoine; D004440:Ecdysone; C055348:muristerone A; D004441:Ecdysterone; C008999:ponasterone A