AWZ1066S, a highly specific anti- Wolbachia drug candidate for a short-course treatment of filariasis
- Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1414-1419. doi: 10.1073/pnas.1816585116.
- 1. Department of Chemistry, University of Liverpool, L69 7ZD Liverpool, United Kingdom.
- 2. Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom.
- 3. Eisai AiM Institute, Eisai, Inc., Andover, MA 01810.
- 4. Drug Safety, Eisai Co., Ltd., 300-2635 Tsukuba, Japan.
- 5. Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca UK, CB2 0AA Cambridge, United Kingdom.
- 6. Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, 53127 Bonn, Germany.
- 7. Department of Chemistry, Imperial College London, SW7 2AZ London, United Kingdom.
- 8. Department of International Health, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom [email protected] [email protected] [email protected].
- 9. Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom; [email protected] [email protected] [email protected].
- 10. Department of Chemistry, University of Liverpool, L69 7ZD Liverpool, United Kingdom; [email protected] [email protected] [email protected].
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using Antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of Infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.