Progress and challenges in the discovery of macrofilaricidal drugs

Abstract

Control of human filarial infections currently depends on chemotherapeutic strategies predominantly directed at microfilariae. Doxycycline therapy in an extended daily dose regimen sterilizes and kills adult stages, but the utility of this drug for routine field use remains an issue of concern. No macrofilaricidal drugs with efficacy after one or two doses are available for use, delaying the achievement of the elimination or eradication of onchocerciasis and lymphatic filariasis. Moxidectin, a macrocyclic lactone, is currently in clinical trials for onchocerciasis. A few other drugs that have already been approved for use in veterinary practice or in human medicine for other indications are available for investigation. Early drug discovery pipelines are poorly populated and the process of macrofilaricide discovery and development remains highly challenging. In particular, the lack of convenient, validated animal models in an antifilarial drug discovery pathway is an unresolved issue.

Keywords::

• anthelmintic
• filarial
• flubendazole
• lymphatic filariasis
• macrocyclic lactone
• nematode
• onchocerciasis

Acknowledgements

This publication stems from work supported by the Bill and Melinda Gates Foundation, the Canada Research Chairs, the Natural Sciences and Engineering Research Council of Canada, and the FQRNT Centre for Host-Parasite Interactions. We sincerely thank Yovany Moreno for preparing the figures.

Financial & competing interests disclosure

The authors are co-investigators on a new grant from the Bill & Melinda Gates Foundation to the Drugs for Neglected Diseases Initiative for support of studies on flubendazole as a macrofilaricide. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.