Ecdysone receptor: A novel target for development of drugs against filariasis

Filariasis is a debilitating disease affecting 120 million people globally caused by filaria.  The massive socio-economic impact of these infections energized the international community to declare a goal at the London Declaration to eliminate filariasis by 2020.  This resulted in a dramatic increase in the efforts to eliminate filariasis employing a strategy of mass drug administration (MDA).  However, these programs rely upon the small arsenal of drugs.  This leaves these programs vulnerable to failure in the face of developing resistance and local intolerance to the current drug regimens.  Thus, new drugs against these infections are critically needed. A homologue of the ecdysone receptor (EcR), a master regulator of development in insects has been identified in B. malayi.  As the EcR is absent in humans, it represents an attractive potential chemotherapeutic target.  The potential of the EcR as a drug target has been underscored by work in the agricultural industry, where insecticides targeting the ecdysone developmental pathway are effective and non-toxic to non-target species.  In initial experiments, structural activity relationship (SAR) modeling identified the diacylhydrazines as potential ecdysone agonists and antogonists.  An high throughput assay was developed to screen for agonists and antagonists of the filarial EcR. The assay was employed to screen steroidal, non-steroidal and natural ecdysone analogs.  A total of 13 agonists and antagonists have been identified. These initial studies pave the way towards the development of agonists and antagonists that can represent lead compounds for the development of a new class of drugs against the human filarial parasites.