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.
W David Hong  1  2 Farid Benayoud  3 Gemma L Nixon  1 Louise Ford  2 Kelly L Johnston  2 Rachel H Clare  2 Andrew Cassidy  2 Darren A N Cook  2 Amy Siu  3 Motohiro Shiotani  4 Peter J H Webborn  5 Stefan Kavanagh  5 Ghaith Aljayyoussi  2 Emma Murphy  2 Andrew Steven  2 John Archer  2 Dominique Struever  6 Stefan J Frohberger  6 Alexandra Ehrens  6 Marc P Hübner  6 Achim Hoerauf  6 Adam P Roberts  2 Alasdair T M Hubbard  2 Edward W Tate  7 Remigiusz A Serwa  7 Suet C Leung  1  2 Li Qie  1 Neil G Berry  1 Fabian Gusovsky  3 Janet Hemingway  8 Joseph D Turner  2 Mark J Taylor  2 Stephen A Ward  9 Paul M O'Neill  10
Affiliations
  • 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].
Abstract

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.

Keywords
anti-Wolbachia; drug discovery; lymphatic filariasis; macrofilaricide; onchocerciasis.
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