1. Academic Validation
  2. AWZ1066S, a highly specific anti- Wolbachia drug candidate for a short-course treatment of filariasis

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

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 janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk pmoneill@liverpool.ac.uk.
  • 9 Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, L3 5QA Liverpool, United Kingdom; janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk pmoneill@liverpool.ac.uk.
  • 10 Department of Chemistry, University of Liverpool, L69 7ZD Liverpool, United Kingdom; janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk pmoneill@liverpool.ac.uk.
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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